Flap modulators

ABSTRACT

The present invention relates to compounds of Formula (I), or a form thereof wherein ring A, R 1 , L and R 2  are as defined herein, useful as FLAP modulators. The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 61/760,615, filed Feb. 4, 2013, and U.S. Provisional Application No. 61/798,951, filed Mar. 15, 2013, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to substituted compounds useful as 5-lipoxygenase-activating protein (FLAP) modulators, pharmaceutical compositions of such compounds, methods of preparation and use thereof. More particularly, FLAP modulators are useful for preventing, treating or ameliorating FLAP-mediated diseases and/or disorders, including those inflammation diseases and/or disorders associated with dermatological and respiratory disorders, allergic disorders, autoimmunity, cancer, cardiovascular and metabolic disorders.

BACKGROUND OF THE INVENTION

FLAP is a key initiator of the leukotriene synthesis pathway that binds and then transfers arachidonic acid to 5-lipoxygenase (M. Abramovitz et al., “5-lipoxygenase-activating protein stimulates the utilization of arachidonic acid by 5-lipoxygenase,” Eur. J. Biochem., 1993, 215, 105-11). FLAP has been demonstrated to interact with LTC₄ synthase, and could putatively modulate the production of LTC₄ (T. Strid et al., “Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein,” Biochem. Biophys. Res. Comm., 2009, 381(4), 518-22). Modulation (including without limitation inhibition) or genetic deletion of FLAP blocks leukotriene production, specifically LTB₄, the cysteinyl leukotrienes (LTC₄, LTD₄ and LTE₄) as well as 5-oxo-ETE (J. Z. Haeggström et al., “Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease,” Chem Rev., 2011, 111(10), 5866-98).

Leukotrienes are immune-modulating lipids formed from arachidonic acid (reviewed in B. Samuelsson, “Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation,” Science, 1983, 220, 568-75). They are synthesized primarily by eosinophils, neutrophils, mast cells, basophils, dendritic cells, macrophages and monocytes. Leukotrienes mediate multiple biological effects including, by way of example only, smooth muscle contraction, leukocyte recruitment and activation, cytokine secretion, fibrosis, mucous secretion, and vascular function (J. Z. Haeggström, at 5866-98).

FLAP-deficient mice are healthy and reproduce normally. They do not produce leukotrienes and have decreased susceptibility in mouse models of arthritis (R. J. Griffiths et al., “Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice,” J. Exp. Med., 1997, 185, 1123-29). In humans, FLAP itself has been linked by genetic studies to respiratory disorders and cardiovascular disease, including myocardial infarction, atherosderosis, cerebral infarctions, coronary artery disease and stroke (A. Helgadottir et al., “The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction, atherosclerosis and stroke,” Nat. Genet., 2004, 36, 233-39; A. S. Tulah et al., “The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers,” BMC Med. Genet., 2011, 29(12), 173; R. Ji et al., “Genetic variants in the promoter region of the ALOX5AP gene and susceptibility of ischemic stroke,” Cerebrovasc. Dis., 2011, 32(3), 261-68; J. W. Holloway et al., “The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility,” Allergy, 2008, 63(8), 1046-53; J. Nair et al., “Expression analysis of leukotriene-inflammatory gene interaction network in patients with coronary artery disease,” J Atheroscler. Thromb., 2013; L. F. Chi et al., “Interaction between ALOX5AP and CYP3A5 gene variants significantly increases the risk for cerebral infarctions in Chinese,” Neuroreport., 2013). In addition, studies using animal models support a causative role for leukotrienes in aortic aneurisms, atherosclerosis, pulmonary arterial hypertension, myocardial infarction, atherosclerosis, and stroke (reviewed in J. Z. Haeggström, at 5866-98).

Leukotrienes also play a role in autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty effusions, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease and multiple sclerosis (S. Chwieśko-Minarowska et al., “The role of leukotrienes in the pathogenesis of systemic sclerosis,” Folia Histochem. Cytobiol., 2012, 50(2), 180-85; M. Rosnowska et al., “Leukotrienes C4 and B4 in cerebrospinal fluid of patients with multiple sclerosis,” Pol. Merkuriusz Lek., 1997, 2, 254-55; and reviewed in J. Z. Haeggström, at 5866-98; I. Loell et al., “Activated LTB4 pathway in muscle tissue of patients with polymyositis or dermatomyositis,” Ann. Rheum. Dis., 2013, 72(2), 293-99; J. Chu et al., “Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer's disease mouse model,” J. Neuroinflammation, 2012, 9, 127). Leukotrienes have also been implicated in several aspects of carcinogenesis including tumor cell proliferation, differentiation, and apoptosis, tumor-associated angiogenesis, as well as the migration and invasion of carcinoma cells (D. Wang and R. N. Dubois, “Eicosanoids and cancer,” Nat. Rev. Cancer, 2010, 10(3), 181-93).

Leukotrienes play a key role in allergic disorders such as allergic rhinitis, allergic dermatitis and asthma, as well as respiratory disorders such as exacerbations, non-allergic asthma, aspirin exacerbated respiratory disease, fibrotic lung diseases, acute respiratory distress syndrome and chronic obstructive pulmonary disease (reviewed in J. Z. Haeggström at 5866-98). Approved antagonists of the LTC₄ receptor and leukotriene synthesis modulators such as zileuton have shown clinical efficacy in a variety of respiratory disorders (reviewed in M. E. Krawiec and S. E. Wenzel, “Leukotriene modulators and non-steroidal therapies in the treatment of asthma,” Expert. Opin. Pharmacotherapy, 2001, 2(1), 47-65).

All the above evidence supports a key role of leukotrienes in a variety of human diseases and/or disorders, and FLAP modulation would be effective for the prevention, treatment, or amelioration of these immune-mediated inflammatory diseases and/or disorders. Furthermore, there still remains a need for FLAP modulator compounds that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides novel compounds useful as, for example, FLAP modulators (including without limitation novel compounds that inhibit FLAP), methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical compositions comprising one or more such compounds, and methods of prophylaxis, treatment, amelioration, including without limitation inhibition, of one or more diseases and/or disorders associated with FLAP using such compounds or pharmaceutical compositions.

One aspect of the present invention is directed to compounds, methods, and compositions for the treatment or prophylaxis or amelioration of a variety of diseases and/or disorders that are mediated or sustained through the activity of leukotrienes, including pulmonary, allergic, fibrotic, neurological, inflammatory, autoimmune and cardiovascular diseases and cancer or associated symptoms or complications thereof. More specifically, this invention is directed to a method of treating exacerbations, non-allergic asthma, fibrotic lung diseases, acute respiratory distress syndrome and chronic obstructive pulmonary disease, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder, wherein the method comprises administering a FLAP modulator.

Another aspect of the present invention is directed to compounds, methods, and compositions for the treatment or prophylaxis or amelioration of cardiac and cardiovascular diseases and/or disorders, or associated symptoms or complications thereof, that include but are not limited to myocardial infarction, atherosclerosis, stroke and atherosclerosis aortic aneurisms, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder, wherein the method comprises administering a FLAP modulator.

Yet another aspect of the present invention is directed to compounds, methods, and compositions for the prophylaxis, treatment, or amelioration of autoimmune diseases and/or disorders, or associated symptoms or complications thereof, that include but are not limited to rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty effusions, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease, multiple sclerosis or allergic disorders that include but are not limited to allergic rhinitis, allergic dermatitis and asthma, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder, wherein the method comprises administering a FLAP modulator.

Finally, one aspect of the present invention is directed to compounds, methods, and compositions for the prophylaxis, treatment, or amelioration of carcinogenesis including but not limited to tumor cell proliferation, differentiation, apoptosis, tumor-associated angiogenesis, as well as the migration and invasion of carcinoma cells, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder, wherein the method comprises administering a FLAP modulator.

Another aspect of the present invention features a compound of Formula (I)

wherein

L is a bond, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂NH—, —CH₂C(═O)NH—, —CH₂C(OH)(H)CH₂—, or —CH₂C(OH)(H)CH₂NH—;

R₁ is halo, C₁₋₄-alkyl, C₃₋₆cycloalkyl, or cyclohexylmethyl;

R₂ is H, C₁₋₄alkyl, hydroxyl, amino, cyano, —CH₂C(═O)O-(tert-butyl), —CH₂C(═O)O-(ethyl), —CH₂C(═O)OH, —NHS(═O)₂CH₃, tert-butyl(dimethyl)silyl-oxy, —NHCH₃, —N(CH₃)₂, —NH-(Isopropyl), optionally substituted phenyl, optionally substituted 5-membered or 6-membered heteroaryl, C₃₋₆cycloalkyl, or optionally substituted heterocyclyl;

wherein the 5-membered or 6-membered heteroaryl, the heterocyclyl, or the phenyl is optionally and independently substituted with 1-4 substituents selected from the group consisting of:

C₁₋₄alkyl, —CH₂-methoxy, —C(═O)OH, —CH₂C(═O)OH, —C(═O)—O—CH₂CH₃, —C(═O)—O—CH₃, —C(═O)—O-(tert-butyl), —NH₂, —NHCH₃, —N(CH₃)₂, —NH-(isobutyl), —NH(CH₂)₂NHC(═O)—O-tert-butyl, —NH(CH₂)₂NH₂, —NH(CH₂)₂N(CH₃)₂, —C(═O)NH₂, —C(═O)CH₃, Oxo, halo, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, methoxymethyl, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂, —S—CH₃, cyano, 1H-tetrazol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl, 4′-(trifluoromethyl) phenyl, benzyl, 1,5-dioxa-9-azaspiro[5.5]undecan-9-yl, 5-pyrimidine-2-amine, and pentafluoro-lambda˜6˜-sulfanyl;

ring A is selected from the group consisting of:

R₃ is H, cyano, methyl, methoxy, halo, or —NH₂;

R₄ is H, or methyl; and

R₅ is H, cyano, halo, CF₃, or —NH₂;

or an optical isomer, hydrate, metabolite, enantiomer, diastereomer, cis-trans isomer, racemate, prodrug or pharmaceutically acceptable salt thereof.

Another aspect of the present invention features a pharmaceutical composition comprising at least one compound of Formula (I) and at least one pharmaceutically acceptable carrier. The invention is also directed towards providing a process for formulating a pharmaceutical composition, comprising formulating a pharmaceutical composition of at least one compound of Formula (I) and at least one pharmaceutically acceptable carrier. The present invention further relates to a process for making a pharmaceutical composition comprising mixing any of the compounds according to Formula (I) and a pharmaceutically acceptable carrier.

The present invention also features a method of treating a subject suffering from or diagnosed with a disease and/or disorder mediated by FLAP activity, comprising administering to the subject a therapeutically effective amount of at least one compound of Formula (I). Such a disease and/or disorder can include, but is not limited to respiratory disorders, cardiac and cardiovascular diseases, autoimmune disorders, carcinogenesis or associated symptoms or complications. More specifically, this invention is directed to a method of treating exacerbations, non-allergic asthma, fibrotic lung diseases, acute respiratory distress syndrome, chronic obstructive pulmonary disease myocardial infarction, atherosclerosis and stroke aortic aneurisms, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty effusions, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease, multiple sclerosis, allergic rhinitis, allergic dermatitis and asthma, tumor cell proliferation, differentiation, and apoptosis, tumor-associated angiogenesis, as well as the migration and invasion of carcinoma cells, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder, or associated symptoms or complications thereof, wherein the method comprises administering a FLAP modulator to a subject in need thereof, a therapeutically effective amount of at least one compound of Formula (I), preferably in a pharmaceutical composition comprising at least one compound of Formula (I).

Additional embodiments and advantages of the invention will become apparent from the detailed discussion, schemes, examples, and claims below.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel FLAP modulators and compositions thereof for the prophylaxis, treatment, or amelioration of numerous diseases and/or disorders, including but not limited to respiratory diseases and/or disorders, cardiac and cardiovascular diseases and/or disorders, autoimmune diseases and/or disorders, carcinogenesis, and associated symptoms or complications thereof.

One aspect of the present invention features a compound of Formula (I)

wherein

L is a bond, —CH₂—, —CH₂CH₂—, —CH₂C(OH)(H)CH₂, —CH₂CH₂CH₂—, —CH₂CH₂NH—, —CH₂C(═O)NH—, or —CH₂C(OH)(H)CH₂NH—;

R₁ is halo, C₁₋₅alkyl, C₃₋₆cycloalkyl, or cyclohexylmethyl;

R₂ is H, C₁₋₄alkyl, hydroxyl, amino, cyano, —CH₂C(═O)O-(tert-butyl), —CH₂C(═O)O-(ethyl), —CH₂C(═O)OH, —NHS(═O)₂CH₃, tert-butyl(dimethyl)silyl-oxy, —NHCH₃, —N(CH₃)₂, —NH-(Isopropyl), optionally substituted phenyl, optionally substituted 5-membered or 6-membered heteroaryl, C₃₋₆cycloalkyl, or optionally substituted heterocyclyl;

wherein the 5-membered or 6-membered heteroaryl, the heterocyclyl, or the phenyl is optionally and independently substituted with 1-4 substituents selected from the group consisting of:

C₁₋₄alkyl, —CH₂-methoxy, —C(═O)OH, —CH₂C(═O)OH, —C(═O)—O—CH₂CH₃, —C(═O)—O—CH₃, —C(═O)—O-(tert-butyl), —NH₂, —NHCH₃, —N(CH₃)₂, —NH-(isobutyl), —NH(CH₂)₂NHC(═O)—O-tert-butyl, —NH(CH₂)₂NH₂, —NH(CH₂)₂N(CH₃)₂, —C(═O)NH₂, —C(═O)CH₃, oxo, halo, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, methoxymethyl, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂, —S—CH₃, cyano, 1H-tetrazol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl, 4′-(trifluoromethyl) phenyl, benzyl, 1,5-dioxa-9-azaspiro[5.5]undecan-9-yl, 5-pyrimidine-2-amine, and pentafluoro-lambda˜6˜-sulfanyl;

ring A is selected from the group consisting of:

R₃ is H, cyano, methyl, methoxy, halo, or —NH₂;

R₄ is H, or methyl; and

R₅ is H, cyano, halo, CF₃, or —NH₂.

Some embodiments of the present invention are given by compounds of Formula (I), wherein R₁ is tert-butyl, cyclopropyl, cyclobutyl, or cyclopentyl, R₃ is H or cyano, R₄ is H, and R₅ is H.

Other embodiments are given by compounds of Formula (I), wherein R₁ is tert-butyl, cyclobutyl, or cyclopentyl.

Yet, other embodiments are given by compounds of Formula (I), wherein R₁ is tert-butyl or cyclobutyl, R₃ is H or cyano, R₄ is H, and R₅ is H.

Some embodiments are given by compounds of Formula (I), wherein ring A is

In some of these embodiments, wherein ring A is

R₃ is cyano, and R₄ is cyano.

In some of these embodiments, wherein ring A is

R₃ is H, and R₄ is H.

Some embodiments are given by compounds of Formula (I), wherein R₁ is tert-butyl.

Some embodiments are given by compounds of Formula (I), wherein R₁ is cyclobutyl.

In some of these embodiments, wherein R₁ is cyclobutyl, R₂ is —CH₂C(═O)O-(tert-butyl), —CH₂C(═O)O-(ethyl), —CH₂C(═O)OH, or —NHS(═O)₂CH₃.

In some of these embodiments, wherein R₁ is cyclobutyl, R₂ is optionally substituted phenyl, or optionally substituted 5-membered or 6-membered heteroaryl.

In some of these embodiments, wherein R₁ is cyclobutyl, L is a bond or —CH₂—.

In some of these embodiments, wherein R₁ is cyclobutyl, ring A is

In some of these embodiments, wherein R₁ is cyclobutyl, ring A is

In some of these embodiments, wherein R₁ is cyclobutyl, ring A is

Some embodiments are given by compounds of Formula (I), wherein L is a bond or —CH₂—.

In some of these embodiments, wherein L is a bond or —CH₂—, R₁ is cyclobutyl, and ring A is

In another embodiment, the present invention includes a compound of Formula (I) wherein:

-   -   L is a bond or —CH₂—;     -   R₁ is tert-butyl or cyclobutyl;     -   R₂ is optionally substituted phenyl or an optionally substituted         6-membered heteroaryl;     -   wherein the substitution of the phenyl or the 6-membered         heteroaryl is selected from a group consisting of:     -   hydroxyl, fluoro, methoxy, cyano, amino, —C(═O)—NH₂, and         pentafluoro-lambda˜6˜-sulfanyl;     -   ring A is

and

-   -   R₃ is H or cyano.

In yet another embodiment, the present invention includes a compound of Formula (I) wherein:

-   -   L is a bond or —CH₂—;     -   R₁ is tert-butyl or cyclobutyl;     -   R₂ is optionally substituted phenyl, optionally substituted         pyridine or optionally substituted pyrimidine;     -   wherein the substitution of the phenyl, the pyridine or the         pyrimidine is selected from a group consisting of:     -   hydroxyl, fluoro, methoxy, cyano, amino, —C(═O)—NH₂, and         pentafluoro-lambda˜6˜-sulfanyl; and     -   ring A is

The embodiments of the present invention also include the optical isomers, hydrates, metabolites, enantiomers, diastereomers, cis-trans isomers, racemates, prodrugs or pharmaceutically acceptable salts thereof.

It is an embodiment of the present invention to provide a compound selected from the compounds listed in Table 1.

TABLE 1 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine, 3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol, 3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin- 2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin- 2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine, 3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid, 4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid, 5-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin- 2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin- 2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2- (trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[3- (trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine, 5-(3-{[4-Chloro-2-(methylsulfonyl)benzyl]oxy}-4-cyclobutyl-2- fluorophenyl)pyrazin-2-amine 1-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]- methyl}phenyl)-ethanone, 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-3-ylmethoxy)phenyl]pyrazin-2-amine, 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-4-ylmethoxy)phenyl]pyrazin-2-amine, 4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}benzonitrile, 3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}benzonitrile, 3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}benzamide, 2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}benzonitrile, 2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}benzamide, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1H-tetrazol-5- yl)benzyl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[3-(1H-tetrazol-5- yl)benzyl)oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-(1H-tetrazol-5- yl)benzyl]oxy}phenyl)pyrazin-2-amine, (4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}phenyl)acetic acid, 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-2-ylmethoxy)phenyl]pyrazin-2-amine, 4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N,N-dimethyl- benzenesulfonamide, 4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-methyl}- benzenesulfonamide, 4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N- methylbenzenesulfonamide, 5-{4-Cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(3-fluorobenzyl)oxy]phenyl}pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(2-fluorobenzyl)oxy]phenyl}pyrazin-2-amine, 5-{4-Cyclobutyl-3-[(2,6-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2- amine, 5-{4-Cyclobutyl-3-[(2,3-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2- amine, 5-{4-Cyclobutyl-3-(3,4-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2- amine, 5-{3-[(2-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine, 5-{3-[(3-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine, 5-{3-[(4-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine, 5-{4-Cyclobutyl-3-[(2,6-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2- amine, 5-{4-Cyclobutyl-3-[(2,5-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2- amine, 5-{4-Cyclobutyl-3-[(2,3-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2- amine, 5-{4-Cyclobutyl-3-[(2,4-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2- amine, 5-{4-Cyclobutyl-3-[(3,4-dimethylbenzyl)oxy]-2-fluorophenyl}pyrazin-2- amine, 5-(3-{[2-Chloro-3-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2- fluorophenyl)pyrazin-2-amine, 5-(3-{[5-Chloro-2-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2- fluorophenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-fluoro-2- (trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine, 5-{3-[(2-Chloro-5-fluorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine, 2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid, 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-pyrazol-3- yl)methoxy]phenyl}pyrazin-2-amine, 5-{4-Cyclobutyl-3-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methoxy]-2- fluorophenyl}pyrazin-2-amine, tert-Butyl [3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetate, [3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetic acid, racemic 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyridin-2(1H)-one, racemic 3-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyrimidin-4(3H)-one, racemic 2-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyridazin-3(2H)-one, racemic 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyrazin-2(1H)-one, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3- (pyrimidin-5-ylamino)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3- (pyrimidin-2-ylamino)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3- (pyrazin-2-ylamino)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((5- aminopyrimidin-2-yl)amino)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((6- aminopyrimidin-4-yl)amino)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H- pyrazol-1-yl)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H- imidazol-1-yl)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H- 1,2,4-triazol-1-yl)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H- 1,2,3-triazol-1-yl)propan-2-ol, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(2H- 1,2,3-triazol-2-yl)propan-2-ol, racemic 5-Amino-1-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile, racemic 1-(5-Amino-1H-1,2,3-triazol-1-yl)-3-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)propan-2-ol, racemic 1-((1H-Pyrazol-5-yl)amino)-3-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)propan-2-ol, 5-(4-Cyclobutyl-2-fluoro-3-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}- phenyl)-pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)-oxy]-phenyl}pyrazin- 2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(5-methyl-1,2,4-oxadiazol-3- yl)methoxy]phenyl}pyrazin-2-amine, 5-[4-Cyclobutyl-3-(cyclohexylmethoxy)-2-fluorophenyl]pyrazin-2-amine, 5-[4-Cyclobutyl-3-(cyclopropylmethoxy)-2-fluorophenyl]pyrazin-2-amine, Ethyl 5-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}furan-2-carboxylate, tert-Butyl 4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]- methyl}-piperidine-1-carboxylate, 5-{4-Cyclobutyl-2-fluoro-3-[(3-methyl-1,2,4-oxadiazol-5-yl)-methoxy]- phenyl}-pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-methoxy-5-(pentafluoro-lambda~6~- sulfanyl)-benzyl]-oxy}-phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-5-(pentafluoro-lambda~6~- sulfanyl)benzyl]-oxy}-phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-4-(pentafluoro-lambda~6~- sulfanyl)benzyl]-oxy}-phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(pentafluoro-lambda~6~-sulfanyl)benzyl]- oxy}-phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[3-(pentafluoro-lambda~6~-sulfanyl)benzyl]- oxy}-phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-(pentafluoro-lambda~6~-sulfanyl)benzyl]- oxy}-phenyl)-pyrazin-2-amine, 5-[4-Cyclobutyl-3-(cyclobutylmethoxy)-2-fluorophenyl]pyrazin-2-amine, 5-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine, 4-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}benzoic acid, 5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2- carboxylic acid, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6- methylpyrimidin-4-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(4-phenylpyrimidin-2-yl)oxy]phenyl}pyrazin-2- amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfanyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine, 5-{4-Cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2- fluorophenyl}pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(4-thiophen-2-ylpyrimidin-2- yl)oxy]phenyl}pyrazin-2-amine, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4- carbonitrile, 5-{4-Cyclobutyl-2-fluoro-3-[(4-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin- 2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(5-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin- 2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6- methylpyrimidin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin- 2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6- methoxypyrimidin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2- methoxypyrimidin-4-amine, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzonitrile, 5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2- yl]oxy}phenyl)pyrazin-2-amine, Methyl 4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoate, 5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrazin-2- yl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridazin-3- yl]oxy}phenyl)pyrazin-2-amine, Methyl 6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine- 3-carboxylate, 5-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2- carbonitrile, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2- carbonitrile, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3- carbonitrile, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2- carbonitrile, 3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2- carbonitrile, 5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyridin-2- yl]oxy}phenyl)pyrazin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3- carbonitrile, 5-{4-Cyclobutyl-2-fluoro-3-[4-(pentafluoro-lambda~6~-sulfanyl)phenoxy]- phenyl}-pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfonyl)phenoxy]phenyl}pyrazin-2- amine, 5-{4-Cyclobutyl-2-fluoro-3-[2-(methylsulfonyl)phenoxy]phenyl}pyrazin-2- amine, 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4- amine, 5-{3-[3,4-Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2- fluorophenyl}pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)pyridin-2- yl]oxy}phenyl)pyrazin-2-amine, 5-{3-[(3-Chloropyridin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine, 5-{3-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-cyclobutyl-2- fluorophenyl}pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)pyrimidin-4- yl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyrimidin-4- yl]oxy}phenyl)pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[3-methyl-4- methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine, 5-(4-cyclobutyl-2-fluoro-3-(4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy)- phenyl)-pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-3- yl]oxy}phenyl)pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(3-methoxypyridin-2-yl)oxy]phenyl}pyrazin-2- amine, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2- amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5- (methylsulfonyl)-benzonitrile, 5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfonyl)-3-(trifluoromethyl)- phenoxy]-phenyl}-pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(2-methylpyrimidin-4-yl)oxy]phenyl}pyrazin-2- amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-(1-methylethyl)pyrimidin-4- yl]oxy}phenyl)pyrazin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4- amine, 5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine, 5-{3-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-4-cyclobutyl-2- fluorophenyl}pyrazin-2-amine trifluoroacetate salt, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,N-dimethyl-2- (trifluoromethyl)pyrimidin-4-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2- methylpyrimidin-4-amine trifluoroacetate salt, 5-{4-Cyclobutyl-3-[(6-cyclopropylpyrimidin-4-yl)oxy]-2- fluorophenyl}pyrazin-2-amine, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6- (methoxymethyl)pyrimidin-2-amine, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6- chloropyrimidin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(2-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2- amine, 5-{4-Cyclobutyl-2-fluoro-3-[(6-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2- amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2- benzylpyrimidin-4-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[6-(1-methylethyl)pyrimidin-4- yl]oxy}phenyl)pyrazin-2-amine, 3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-1-methyl-5- (trifluoromethyl)-1H-pyrazole-4-carbonitrile, tert-Butyl [2-({2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]pyrimidin-4-yl}amino)ethyl]carbamate, N-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2- yl}ethane-1,2-diamine, Methyl 2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]pyrimidine-4-carboxylate trifluoroacetate salt, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4- carboxylic acid, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoic acid, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3- carboxylic acid, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzamide, N′-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2- yl}-N,N-dimethylethane-1,2-diamine hydrochloride, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4- carboxamide, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-5- amine, 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrimidin-2-amine, 3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol, 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine, 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2- amine, 4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]-6- (methoxymethyl)pyrimidin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrimidin- 2-amine, 5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2- amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2- yl]oxy}phenyl)pyrimidin-2-amine, 4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2- amine, 5-{4-Cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2- fluorophenyl}pyrimidin-2-amine, 4-(3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy)-6- isopropylpyrimidin-2-amine, 2-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4- carboxamide, 5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4- yl)oxy)phenyl)pyrimidin-2-amine trifluoroacetate salt, 6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol trifluoroacetate salt, 6-Amino-3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2- carbonitrile, 6-Amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile, 3-{[3-(5-Amino-3-cyanopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}benzoic acid, 2-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine, 6-Cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol, 2-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-5H- pyrrolo[2,3-b]pyrazine trifluoroacetate salt, 2-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine, 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyridin-2-amine hydrochloride salt, 5-(4-Cyclobutyl-2-fluoro-3-hydroxyphenyl)pyridin-2-amine, 5-Methyl-4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2- fluorophenoxy)methyl)benzoate, 4-((3-(6-Aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoic acid, 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyrazine, 6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine, 7-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine, 6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenol, 7-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine, 3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}benzonitrile, 7-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazine, 7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazine, 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}benzonitrile, 7-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazine, 3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}benzamide, 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}benzamide, 7-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazine, (4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}phenyl)acetic acid, 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}benzoic acid, 3-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine, 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine, 6-Cyclobutyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol, 3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenol, 5-(4-tert-Butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrazin-2- amine, 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4- amine, 2-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4- amine, 5-{4-tert-Butyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2- amine, 5-(4-tert-Butyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine, 3-(2-Aminopyrimidin-5-yl)-6-tert-butyl-2-fluorophenol, 5-(4-tert-Butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrimidin-2- amine, 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine, 5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2- amine, 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2- amine, 5-(4-Cyclopentyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine, 5-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]pyrazin-2-amine, 5-[4-Cyclopentyl-2-fluoro-3-(1-methylethoxy)phenyl]pyrazin-2-amine, 2-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine, 5-[3-(Benzyloxy)-4-tert-butylphenyl]pyrazin-2-amine, 5-[3-(Benzyloxy)-4-cyclobutylphenyl]pyrazin-2-amine, 3-amino-6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2- carbonitrile, 6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyridazin-3-amine, 6-cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol, 6-cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol, 3-amino-6-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile, 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol, 7-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine, 2-(6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy)pyrimidin-4-amine, 7-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazine, 5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-1H- pyrrolo[2,3-b]pyridine, 2-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-5H- pyrrolo[2,3-b]pyrazine, 2-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-5H-pyrrolo[2,3- b]pyrazine, 6-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridazin-3-amine, 6-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4- yl)oxy)phenyl)pyridazin-3-amine, 6-(3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidin-4-ol, 4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidine-2- carbonitrile, 6-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N,2- trimethylpyrimidin-4-amine, 4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N,6- trimethylpyrimidin-2-amine, 6-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N- dimethylpyrimidin-4-amine, Ethyl 5-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-1-methyl- 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 5-(4-cyclobutyl-2-fluoro-3-((5-(methylsulfonyl)pyridin-2- yl)oxy)phenyl)pyrazin-2-amine, 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-(tert- butyl)pyrimidin-2-amine, 5-(3-((4-(1,5-dioxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-2-yl)oxy)-4- cyclobutyl-2-fluorophenyl)pyrazin-2-amine, 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6- isobutylpyrimidin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine, N-(2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-ethyl)- methane-sulfonamide, 5-(4-Cyclobutyl-2-fluoro-3-(2-morpholinoethoxy)phenyl)pyrazin-2-amine, Ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate, tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy)methyl)-azetidine-1-carboxylate, tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy)methyl)-pyrrolidine-1-carboxylate, tert-Butyl 2-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy)methyl)-pyrrolidine-1-carboxylate, tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)- methyl)-piperidine-1-carboxylate, 2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)ethanol, 4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoic acid, 5-(4-Cyclobutyl-2-fluoro-3-((tetrahydrofuran-2-yl)methoxy)phenyl)pyrazin- 2-amine, racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3- (isobutylamino)-propan-2-ol, racemic 3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy)propane-1,2-diol, racemic 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3- morpholinopropan-2-ol, racemic 4-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)-thiomorpholine 1,1-dioxide, 5-(4-Cyclobutyl-2-fluoro-3-(pyridazin-4-yloxy)phenyl)pyrazin-2-amine, 3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrazin-2- amine, 5-(4-Cyclobutyl-2-fluoro-3-(pyrazin-2-yloxy)phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-4-yloxy)phenyl)pyrazin-2-amine, and 4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N-isobutylpyrimidin-2- amine trifluoroacetic acid salt.

Particularly, an embodiment of the present invention comprises a compound selected from the compounds listed in Table 2.

TABLE 2 5-(4-Cyclobutyl-2-fluoro-3-{[2-(pentafluoro-lambda~6~-sulfanyl)benzyl]- oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[3-(pentafluoro-lambda~6~-sulfanyl)benzyl]- oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(pentafluoro-lambda~6~- sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-4-(pentafluoro-lambda~6~- sulfanyl)-benzyl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-flupro-5-(pentafluoro-lambda~6~- sulfanyl)benzyl]oxy-}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-methoxy-5-(pentafluoro-lambda~6~- sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3- carbonitrile, 5-{4-Cyclobutyl-2-fluoro-3-[4-(pentafluoro-lambda~6~- sulfanyl)phenoxy]phenyl}pyrazin-2-amine, 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-4- amine, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2- amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4- amine, 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine, 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}- pyrimidin-2-amine, 5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}- pyrimidin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4- ol, 4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6- methoxypyrimidin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2- methoxypyrimidin-4-amine, 4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin- 2-amine, 6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4- ol trifluoroacetate, 2-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4- amine, 5-{4-Cyclobutyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}- pyrazin-2-amine, 5-{4-tert-Butyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}- pyrazin-2-amine, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-5- amine, 2-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine- 4-carboxamide, 5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-tert-butyl-2-fluorophenyl}- pyrimidin-2-amine, 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-tert-butyl-2-fluorophenyl}- pyrimidin-2-amine, 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine, 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine, and 6-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4- amine.

It is an embodiment of the present invention to provide a compound selected from the compounds listed in Table 1A.

TABLE 1A 3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenol, 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3- b]pyridine, 5-{3-[(2-Aminopyridin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine, 5-{3-[(6-Aminopyrazin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine, 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-5-yloxy)phenyl]pyrazin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-4- amine, 3-(5-Aminopyrazin-2-yl)-6-cyclonexyl-2-fluorophenol, 3-(5-Aminopyrazin-2-yl)-6-(cyclohexylmethyl)-2-fluorophenol, 5-[4-Cyclopentyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2- amine, 5-[4-Cyclopentyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine, 2-[3-(5-Aminopyrazin-2-yl)-6-cyclopentyl-2-fluorophenoxy]pyrimidin-4- amine, 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclopentyl-2-fluorophenyl}- pyrimidin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-3- amine, 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-ylmethoxy)phenyl]pyrazin-2- amine, 5-{3-[(4-Bromobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine, 5-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]methyl}phenyl)pyrimidin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4′-(trifluoromethyl)biphenyl-4- yl]methoxy}phenyl)pyrazin-2-amine, 5-[4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine, 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclonexyl-2-fluorophenyl}- pyrimidin-2-amine.

It is another embodiment of the present invention to provide a compound selected from the compounds listed in Table 1, Table 2 and Table 1A.

The invention is also directed to a pharmaceutical composition which include, without limitation, one or more of the disclosed compounds herein, and pharmaceutically acceptable carriers or excipients.

Another embodiment of the present invention is a pharmaceutical composition of the present invention that comprises at least a compound selected from the compounds listed in Table 1. Another embodiment of the present invention is a pharmaceutical composition of the present invention that comprises at least a compound selected from the compounds listed in Table 3.

Particularly, an embodiment of the present invention is a pharmaceutical composition of the present invention that comprises at least a compound selected from the compounds listed in Table 2.

The present invention also features a method of treating a subject suffering from or diagnosed with a disease and/or disorder mediated by FLAP activity, comprising administering to the subject a therapeutically effective amount of at least one compound of Formula (I).

The present invention also features a method for preventing, treating, ameliorating, including without limitation inhibiting, the progression of an FLAP-mediated disease and/or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of at least one compound of Formula (I). Such a disease and/or disorder includes, but is not limited to diabetes, respiratory disorders, and associated symptoms or complications thereof. More specifically, this invention is directed to a method of treating, but not limited to, exacerbations, non-allergic asthma, fibrotic lung diseases, acute respiratory distress syndrome and chronic obstructive pulmonary disease, and their associated symptoms or complications, in a subject afflicted with such a disease and/or disorder.

In another embodiment, the compounds of the present invention are useful for the amelioration of symptoms associated with and/or the treatment of the following cardiac and cardiovascular diseases and/or disorders: myocardial infarction, atherosclerosis, atherosclerosis and stroke aortic aneurisms, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder.

In another embodiment, the compounds of the present invention are useful for the amelioration of symptoms associated with and/or the treatment of autoimmune or allergic diseases and/or disorders, wherein said autoimmune or allergic diseases and/or disorders include, but are not limited to, rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty effusions, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease, multiple sclerosis, allergic rhinitis, allergic dermatitis and asthma, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder.

In a further embodiment, the compounds of the present invention are useful for the amelioration of symptoms associated with and/or the prophylaxis or treatment of carcinogenesis, wherein said carcinogenesis include, but is not limited to, tumor cell proliferation, differentiation, apoptosis, tumor-associated angiogenesis, as well as the migration and invasion of carcinoma cells.

It is a further embodiment of the invention to provide a process for making a pharmaceutical composition comprising admixing any of the compounds according to Formula (I) and a pharmaceutically acceptable carrier.

In a further embodiment of the invention, a method for treating or ameliorating an FLAP-mediated disease and/or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of at least one compound of Formula (I), wherein the therapeutically effective amount of the compound of Formula (I) is from about 0.1 mg/dose to about 5 g/dose. In particular, the therapeutically effective amount of the compound of Formula (I) is from about 0.5 mg/dose to about 1000 mg/dose.

More particularly, the therapeutically effective amount of the compound of Formula (I) is from about 1 mg/dose to about 100 mg/dose. In a further embodiment of the invention, the number of doses per day of a compound of Formula (I) is from 1 to 3 doses. In a further embodiment of the invention, the therapeutically effective amount of the compound of Formula (I) is from about 0.001 mg/kg/day to about 30 mg/kg/day. More particularly, the therapeutically effective amount of the compound of Formula (I) is from about 0.01 mg/kg/day to about 2 mg/kg/day.

The invention is further described below.

A) Terms

Some terms are defined below and by their usage throughout this disclosure.

It should also be noted that any atom with unsatisfied valences in the text, schemes, examples, structural formulae and any tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences.

As used herein, the following terms are intended to have the following definitions. The definitions herein may specify that a chemical term has an indicated formula. The particular formula provided is not intended to limit the scope of the invention, but is provided as an illustration of the term. The scope of the per se definition of the term is intended to include the plurality of variations expected to be included by one of ordinary skill in the art.

The term “C_(1-n)alkyl” means a saturated branched or straight-chain hydrocarbon radical having from 1 up to n carbon atoms, wherein n is 4 or 5, in a linear or branched arrangement. Examples include methyl, ethyl, 1-propyl, 2-propyl, isobutyl, tert-butyl, isopentyl, neopentyl, pentan-3-yl, and the like, and all that are exemplified in the below examples. An alkyl radical may be attached to a core molecule by any atom where allowed by available valences.

The term “C₃₋₆cycloalkyl” means a saturated or partially unsaturated, monocyclic, hydrocarbon ring system radical. Examples include cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl and the like, and all that are exemplified in the below examples. A C₃₋₅cycloalkyl radical may be attached to a core molecule by any ring atom where allowed by available valences.

The term “aryl” means an unsaturated, aromatic monocyclic or polycyclic hydrocarbon ring system radical. Examples include phenyl and the like, and all that are exemplified in the below examples. An aryl radical may be attached to a core molecule by any ring atom where allowed by available valences.

The term “hetero”, when used as a prefix for a ring system, refers to the replacement of at least one carbon atom member in the ring system with a heteroatom selected from N, O, S, S(O), or SO₂. A hetero ring may have 1, 2, 3 or 4 carbon atom members replaced by a nitrogen atom. Alternatively, a ring may have 1, 2 or 3 nitrogen atom members and 1 oxygen or sulfur atom member. Alternatively, a ring may have 1 oxygen or sulfur atom member. Alternatively, up to two adjacent ring members may be heteroatoms, wherein one heteroatom is nitrogen and the other heteroatom is selected from N, S or O.

The term “heteroaryl” means an unsaturated monocyclic, polycyclic aromatic “hetero” ring system radical, selected from the group consisting of pyrazolyl, oxadiazolyl, furanyl, imidazolyl, imidazolidinyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, quinazolinyl, benzothiazolyl, isoxazolyl, thiazolyl, oxazolyl, thiazolopyridyl, thienopyrimidinyl and isoindolyl. Examples include 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, furan-2-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazolidin-1-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-2-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-4-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, pyridin-3-yl, pyrimidin-1-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-1-yl, pyrazin-2-yl, pyrazin-3-yl, benzimidazol-1-yl, benzoxazol-2-yl, quinoxalin-2-yl, quinazolin-2-yl, benzothiazol-2-yl, isoxazol-3-yl, 1,3-thiazol-4-yl, 1,3-oxazol-2-yl, isoindol-1-yl, thiazolo[4,5-b]pyridyl, thieno[2,3-d]pyrimidinyl and the like, and all that are exemplified in the below examples. A heteroaryl radical may be attached to a core molecule by any ring atom where allowed by available valences.

The term “heterocyclyl” means a saturated monocyclic “hetero” ring system radical, selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, and tetrahydro-2H-pyranyl. Examples include azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, tetrahydro-2H-pyran-4-yl, and the like, and all that are exemplified in the below examples. A heterocyclyl radical may be attached to a core molecule by any ring atom where allowed by available valences.

The term “carboxy” means a radical of the formula: —C(O)OH.

The term “halogen” or “halo” means a radical selected from the group consisting of chloro, bromo, fluoro or iodo.

The term “oxo” means a radical of the formula: ═O.

The term “substituted” refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). In a preferred embodiment, up to three hydrogen atoms are each independently replaced.

With reference to substituents, the term “independently” means that when more than one of such substituent is possible, such substituents may be the same or different from each other.

It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

In general, unless specified otherwise, IUPAC nomenclature rules are used herein.

The term “about,” whether used explicitly or not in reference to a quantitative expression given herein, means that every quantity given herein qualified with the term or otherwise is meant to refer both to the actual given value and the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to experimental and/or measurement conditions for such given value.

The term “form” means, in reference to compounds of the present invention, such may exist as, without limitation, a salt, stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester, prodrug or metabolite form. The present invention encompasses all such compound forms and mixtures thereof.

The term “isolated form” means, in reference to compounds of the present invention, such may exist in an essentially pure state such as, without limitation, an enantiomer, a racemic mixture, a geometric isomer (such as a cis or trans stereoisomer), a mixture of geometric isomers, and the like. The present invention encompasses all such compound forms and mixtures thereof.

The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “subject” as used herein, refers to a patient, such as an animal, a mammal or a human, who has been the object of treatment, observation or experiment and is at risk of (or susceptible to) developing an FLAP-mediated disorder.

The term “administering” further means that the individual ingredients to be combined may be administered at the same time or at different times during the treatment period, either as one preparation or as different preparations. Accordingly, the invention should be so interpreted that it encompasses any and every administration mode at the same time or at different times. The range of the combination of the compound of the invention and the other therapeutic agent useful for the above-mentioned disorders encompasses, in principle, all combinations of the compound of the invention and any and every pharmaceutical agent useful for the above-mentioned disorders.

The term “treating” refers, without limitation, to facilitating the eradication of, preventing, ameliorating or otherwise inhibiting the progression of or promoting stasis of an FLAP-mediated disease and/or disorder, or associated symptoms or complications thereof.

The term “prodrug” means a compound of Formula (I) or a form thereof that is converted in vivo into a functional derivative form that may contribute to therapeutic biological activity, wherein the converted form may be: 1) a relatively active form; 2) a relatively inactive form; 3) a relatively less active form; or, 4) any form which results, directly or indirectly, from such in vivo conversions. Prodrugs are useful when said compound may be either too toxic to administer systemically, absorbed poorly by the digestive tract or broken down by the body before it reaches its target. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in, for example, “Design of Prodruas”, ed. H. Bundgaard, Elsevier, 1985.

The term “metabolite” means a prodrug form of a compound of Formula (I) or a form thereof converted by in vivo metabolism or a metabolic process to a relatively less active functional derivative of said compound.

The term “medicament” or “medicine” refers to a product containing a compound of Formula (I) or a form thereof. The present invention includes use of such a medicament for treating an FLAP-mediated disorder.

The term “combination form” refers to the use of a combination product comprising a compound of Formula (I) or a form, pharmaceutical composition, medicine or medicament thereof and at least one therapeutic agent for treating an FLAP-mediated disorder.

Methods are known in the art for determining effective doses for therapeutic and prophylactic purposes for the disclosed pharmaceutical compositions or the disclosed drug combinations, whether or not formulated in the same composition.

For therapeutic purposes, the term “therapeutically effective amount” or “effective amount” as used herein, means that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease and/or disorder being treated. For prophylactic purposes (i.e., inhibiting the progression of a disorder), the term “therapeutically effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that treats or inhibits in a subject the progression of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician. Thus, the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional drugs according to the invention; or (c) both (or more) drugs are administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together. The effective amount of said compound is from about 0.001 mg/kg/day to about 300 mg/kg/day.

Advantageously, the effective amount of a combination product for treating an FLAP-mediated disease and/or disorder, or associated symptoms or complications thereof, may be a reduced amount of either or both, the compound or therapeutic agent, compared to the effective amount of the compound or therapeutic agent otherwise recommended for treating the disease and/or disorder, or associated symptoms or complications thereof. Therefore, it is contemplated that the compound is administered to the subject before, during or after the time the agent is administered.

The term “pharmaceutically acceptable salt” refers to non-toxic pharmaceutically acceptable salts (Ref. Int'l J. Pharm., 1986, 33: 201-217; J. Pharm. Sci., 1997 (January), 66(1): 1). Other salts well known to those in the art may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the “pharmaceutically acceptable salts” of the compounds of this invention refer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable salt forms include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of an acid such as acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, malonic acid, phosphoric acid, saccharinic acid, succinic acid, sulphuric acid, tartaric acid, trifluoroacetic acid and the like.

Furthermore when the compounds of the present invention carry an acidic moiety, suitable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Edition, John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known in the art. The scope of the present invention encompasses all such protected compound forms and mixtures thereof.

The invention includes compounds of various isomers and mixtures thereof. The term “isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. Such substances have the same number and kind of atoms but differ in structure. The structural difference may be in constitution (geometric isomers) or in an ability to rotate the plane of polarized light (optical isomers).

The term “stereoisomer” refers to isomers that have the same molecular formula and the same sequence of covalently bonded atoms but a different spatial orientation.

The term “optical isomer” means isomers of identical constitution that differ only in the spatial arrangement of their groups. Optical isomers rotate the plane of polarized light in different directions. The term “optical activity” means the degree to which an optical isomer rotates the plane of polarized light.

The term “racemate” or “racemic” means an equimolar mixture of two enantiomeric species, wherein each of the isolated species rotates the plane of polarized light in the opposite direction such that the mixture is devoid of optical activity.

The term “enantiomer” means an isomer having a nonsuperimposable mirror image. The term “diastereomer” means stereoisomers that are not enantiomers.

The term “chiral” means a molecule that, in a given configuration, cannot be superimposed on its mirror image. This is in contrast to achiral molecules that can be superimposed on their mirror images.

The two distinct mirror image versions of the chiral molecule are also known as levo (left-handed), abbreviated L, or dextro (right-handed), abbreviated D, depending on which way they rotate polarized light. The symbols “R” and “S” represent the configuration of groups around a stereogenic carbon atom(s).

The term “geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Substituent atoms (other than hydrogen) on each side of a carbon-carbon double bond may be in an E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the “E” configuration, the substituents having the highest priorities are on opposite sides in relationship to the carbon-carbon double bond. In the “Z” configuration, the substituents having the highest priorities are oriented on the same side in relationship to the carbon-carbon double bond.

Substituent atoms (other than hydrogen) attached to a ring system may be in a “cis” or “trans” configuration. In the “cis” configuration, the substituents are on the same side in relationship to the plane of the ring; in the “trans” configuration, the substituents are on opposite sides in relationship to the plane of the ring. Compounds having a mixture of “cis” and “trans” species are designated “cis/trans”.

The isomeric descriptors (“R,” “S,” “E,” and “Z”) indicate atom configurations and are intended to be used as defined in the literature.

The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include combining the free base (or free acid) of each isomer of an isomeric pair using an optically active acid (or base) to form an optically active salt (followed by fractional crystallization and regeneration of the free base), forming an ester or amide of each of the isomers of an isomeric pair by reaction with an appropriate chiral auxiliary (followed by fractional crystallization or chromatographic separation and removal of the chiral auxiliary), or separating an isomeric mixture of either an intermediate or a final product using various well known chromatographic methods.

Furthermore, compounds of the present invention may have one or more polymorph or amorphous crystalline forms and, as such, are intended to be included in the scope of the invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents (e.g., organic esters such as ethanolate and the like) and, as such, are also intended to be encompassed within the scope of this invention.

B) Compounds

Representative compounds of the present invention are listed in Table 3 below.

TABLE 3 COM- POUND STRUCTURE # NAME

A 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)pyrazin-2-amine

B 3-(5-Aminopyrazin-2-yl)-6-cyclobutyl- 2-fluorophenol

1 5-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethyl)benzyl]oxy}phenyl)- pyrazin-2-amine

2 5-(4-Cyclobutyl-2-fluoro-3-{[3- (trifluoromethyl)benzyl]oxy}phenyl)- pyrazin-2-amine

3 5-(4-Cyclobutyl-2-fluoro-3-{[2- (trifluoromethyl)benzyl]oxy}phenyl)- pyrazin-2-amine

4 3-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzoic acid

5 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzoic acid

6 5-(4-Cyclobutyl-2-fluoro-3-{[3- (methylsulfonyl)benzyl]oxy}phenyl)- pyrazin-2-amine

7 5-(4-Cyclobutyl-2-fluoro-3-{[4- (methylsulfonyl)benzyl]oxy}phenyl)- pyrazin-2-amine

8 5-(4-Cyclobutyl-2-fluoro-3-{[2- (trifluoromethoxy)benzyl]oxy}phenyl)- pyrazin-2-amine

9 5-(4-Cyclobutyl-2-fluoro-3-{[3- (trifluoromethoxy)benzyl]oxy}phenyl)- pyrazin-2-amine

10 5-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethoxy)benzy]oxy}phenyl)- pyrazin-2-amine

11 5-(3-{[4-Chloro-2- (methylsulfonyl)benzyl]oxy}-4- cyclobutyl-2-fluorophenyl)pyrazin-2- amine

12 1-(4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}phenyl)ethanone

13 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-3- ylmethoxy)phenyl]pyrazin-2-amine

14 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-4- ylmethoxy)phenyl]pyrazin-2-amine

15 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzonitrile

16 3-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzonitrile

17 3-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzamide

18 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzonitrile

19 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzamide

20 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1H- tetrazol-5- yl)benzyl]oxy}phenyl)pyrazin-2-amine

21 5-(4-Cyclobutyl-2-fluoro-3-{[3-(1H- tetrazol-5- yl)benzyl]oxy}phenyl)pyrazin-2-amine

22 5-(4-Cyclobutyl-2-fluoro-3-{[2-(1H- tetrazol-5- yl)benzyl]oxy}phenyl)pyrazin-2-amine

23 (4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}phenyl)acetic acid

24 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-2- ylmethoxy)phenyl]pyrazin-2-amine

25 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}- N,N-dimethylbenzenesulfonamide

26 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzenesulfon- amide

27 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}- N-methylbenzenesulfonamide

28 5-{4-Cyclobutyl-2-fluoro-3-[(4- fluorobenzyl)oxy]phenyl}pyrazin-2- amine

29 5-{4-Cyclobutyl-2-fluoro-3-[(3- fluorobenzyl)oxy]phenyl}pyrazin-2- amine

30 5-{4-Cyclobutyl-2-fluoro-3-[(2- fluorobenzyl)oxy]phenyl}pyrazin-2- amine

31 5-{4-Cyclobutyl-3-[(2,6- difluorobenzyl)oxy]-2- fluorophenyl}pyrazin-2-amine

32 5-{4-Cyclobutyl-3-[(2,3- difluorobenzyl)oxy]-2- fluorophenyl}pyrazin-2-amine

33 5-{4-Cyclobutyl-3-[(3,4- difluorobenzyl)oxy]-2- fluorophenyl}pyrazin-2-amine

34 5-{3-[(2-Chlorobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

35 5-{3-[(3-Chlorobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

36 5-{3-[(4-Chlorobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

37 5-{4-Cyclobutyl-3-[(2,6- dichlorobenzyl)oxy]-2- fluorophenyl}pyrazin-2-amine

38 5-{4-Cyclobutyl-3-[(2,5- dichlorobenzyl)oxy]-2- fluorophenyl}pyrazin-2-amine

39 5-{4-Cyclobutyl-3-[(2,3- dichlorobenzy)oxy]-2- fluorophenyl}pyrazin-2-amine

40 5-{4-Cyclobutyl-3-[(2,4- dichlorobenzyl)oxy]-2- fluorophenyl}pyrazin-2-amine

41 5-{4-Cyclobutyl-3-[(3,4- dimethybenzyl)oxy]-2- fluorophenyl}pyrazin-2-amine

42 5-(3-{[2-Chloro-3- (trifluoromethyl)benzyl]oxy}-4- cyclobutyl-2-fluorophenyl)pyrazin-2- amine

43 5-(3-{[5-Chloro-2- (trifluoromethyl)benzyl]oxy}-4- cyclobutyl-2-fluorophenyl)pyrazin-2- amine

44 5-(4-Cyclobutyl-2-fluoro-3-{[4-fluoro- 2- (trifluoromethyl)benzyl]oxy}phenyl) pyrazin-2-amine

45 5-{3-[(2-Chloro-5-fluorobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

46 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}benzoic acid

47 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl- 1H-pyrazol-3- yl)methoxy]phenyl}pyrazin-2-amine

48 5-{4-Cyclobutyl-3-[(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)methoxy]-2- fluorophenyl}pyrazin-2-amine

49 tert-Butyl [3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]acetate

50 [3-(5-Aminopyrazin-2-yl)-6-cyclobutyl- 2-fluorophenoxy]acetic acid

51 racemic 1-(3-(3-(5-Aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyridin-2(1H)-one

52 racemic 3-(3-(3-(5-Aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyrimidin-4(3H)-one

53 racemic 2-(3-(3-(5-Aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyridazin-3(2H)-one

54 racemic 1-(3-(3-(5-Aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyrazin-2(1H)one

55 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3- (pyrimidin-5-ylamino)propan-2-ol

56 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3- (pyrimidin-2-ylamino)propan-2-ol

57 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3- (pyrazin-2-ylamino)propan-2-ol

58 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-((5- aminopyrimidin-2-ylamino)propan-2- ol

59 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-((6- aminopyrimidin-4-yl)amino)propan-2- ol

60 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(1H- pyrazol-1-yl)propan-2-ol

61 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(1H- imidazol-1-yl)propan-2-ol

62 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(1H- 1,2,4-triazol-1-yl)propan-2-ol

63 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(1H- 1,2,3-triazol-1-yl)propan-2-ol

64 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(2H- 1,2,3-triazol-2-yl)propan-2-ol

65 racemic 5-Amino-1-(3-(3-(5- aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy)-2-hydroxypropyl)-1H- pyrazole-4-carbonitrile

66 racemic 1-(5-Amino-1H-1,2,3-triazol- 1-yl)-3-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)propan-2- ol

67 racemic 1-((1H-Pyrazol-5-yl)amino)- 3-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)propan-2- ol

68 5-(4-Cyclobutyl-2-fluoro-3-{[1- (methylsulfonyl)piperidin-4- yl]methoxy}phenyl)pyrazin-2-amine

69 5-{4-Cyclobutyl-2-fluoro-3-[(4- methylpyrimidin-2- yl)oxy]phenyl}pyrazin-2-amine

70 racemic 5-{4-Cyclobutyl-2-fluoro-3- [(5-methyl-1,2,4-oxadiazol-3- yl)methoxy]phenyl}pyrazin-2-amine

71 5-[4-Cyclobutyl-3- (cyclohexylmethoxy)-2- fluorophenyl]pyrazin-2-amine

72 5-[4-Cyclobutyl-3- (cyclopropylmethoxy)-2- fluorophenyl]pyrazin-2-amine

73 Ethyl 5-{[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}furan-2- carboxylate

74 tert-Butyl 4-{[3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2- fluorophenoxy]methyl}piperidine-1- carboxylate

75 5-{4-Cyclobutyl-2-fluoro-3-[(3-methyl- 1,2,4-oxadiazol-5- yl)methoxy]phenyl}pyrazin-2-amine

76 5-(4-Cyclobutyl-2-fluoro-3-{[2- methoxy-5-(pentafluoro-lambda~6~- sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

77 5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro- 5-(pentafluoro-lambda~6~- sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

78 5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro- 4-(pentafluoro-lambda~6~- sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

79 5-(4-Cyclobutyl-2-fluoro-3-{[4- (pentafluoro-lambda~6~- sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

80 5-(4-Cyclobutyl-2-fluoro-3-{[3- (pentafluoro-lambda~6~- sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

81 5-(4-Cyclobutyl-2-fluoro-3-{[2- (pentafluoro-lambda~6~- sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

82 5-[4-Cyclobutyl-3- (cyclobutylmethoxy)-2- fluorophenyl]pyrazin-2-amine

83 5-[3-(Benzyloxy)-4-cyclobutyl-2- fluorophenyl]-pyrazin-2-amine

84 4-{2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]ethyl}benzoic acid

85 5-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}furan-2- carboxylic acid

86 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-6- methylpyrimidin-4-amine

87 5-{4-Cyclobutyl-2-fluoro-3-[(4- phenylpyrimidin-2- yl)oxy]phenyl}pyrazin-2-amine

88 5-(4-Cyclobutyl-2-fluoro-3-{[4- (methylsulfanyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine

89 5-{4-Cyclobutyl-3-[(4,6- dimethylpyrimidin-2-yl)oxy]-2- fluorophenyl}pyrazin-2-amine

90 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1- methylethyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine

91 5-{4-Cyclobutyl-2-fluoro-3-[(4- thiophen-2-ylpyrimidin-2- yl)oxy]phenyl}pyrazin-2-amine

92 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]pyrimidine-4- carbonitrile

93 5-{4-Cyclobutyl-2-fluoro-3-[(4- methoxypyrimidin-2- yl)oxy]phenyl}pyrazin-2-amine

94 5-{4-Cyclobutyl-2-fluoro-3-[(5- methoxypyrimidin-2- yl)oxy]phenyl}pyrazin-2-amine

95 5-(4-Cyclobutyl-2-fluoro-3-{[4- (methylsulfonyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine

96 4-[3-(5-Aminopyrazin-2-y)-6- cyclobutyl-2-fluorophenoxy]-6- methylpyrimidin-2-amine

97 5-{4-Cyclobutyl-2-fluoro-3-[(6- methoxypyrimidin-4- yl)oxy]phenyl}pyrazin-2-amine

98 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 4-ol

99 4-[3-(5-Aminopyrazin-2-y)-6- cyclobutyl-2-fluorophenoxy]-6- methoxypyrimidin-2-amine

100 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-2- methoxypyrimidin-4-amine

101 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]benzonitrile

102 5-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyridin-2- yl]oxy}phenyl)pyrazin-2-amine

103 Methyl 4-[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]benzoate

104 5-(4-Cyclobutyl-2-fluoro-3-{[5- (trifluoromethyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine

105 5-(4-Cyclobutyl-2-fluoro-3-{[5- (trifluoromethyl)pyrazin-2- yl]oxy}phenyl)pyrazin-2-amine

106 5-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyridazin-3- yl]oxy}phenyl)pyrazin-2-amine

107 Methyl 6-[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine- 3-carboxylate

108 5-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine- 2-carbonitrile

109 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine- 2-carbonitrile

110 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine- 3-carbonitrile

111 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine- 2-carbonitrile

112 3-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine- 2-carbonitrile

113 5-(4-Cyclobutyl-2-fluoro-3-{[5- (trifluoromethyl)pyridin-2- yl]oxy}phenyl)pyrazin-2-amine

114 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine- 3-carbonitrile

115 5-{4-Cyclobutyl-2-fluoro-3-[4- (pentafluoro-lambda~6~- sulfanyl)phenoxy]phenyl}pyrazin-2- amine

116 5-{4-Cyclobutyl-2-fluoro-3-[4- (methylsulfonyl)phenoxy]phenyl} pyrazin-2-amine

117 5-{4-Cyclobutyl-2-fluoro-3-[2- (methylsulfonyl)phenoxy]phenyl} pyrazin-2-amine

118 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin- 2-yloxy)phenyl]pyrazin-2-amine

119 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 4-amine

120 5-{3-[3,4- Bis(trifluoromethyl)phenoxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

121 5-(4-Cyclobutyl-2-fluoro-3-{[3- (trifluoromethy)pyridin-2- yl]oxy}phenyl)pyrazin-2-amine

122 5-{3-[(3-Chloropyridin-2-yl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

123 5-{3-[2-Chloro-4- (methylsulfonyl)phenoxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

124 5-(4-Cyclobutyl-2-fluoro-3-{[2- (trifluoromethyl)pyrimidin-4- yl]oxy}phenyl)pyrazin-2-amine

125 5-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyrimidin-4- yl]oxy}phenyl)pyrazin-2-amine

126 5-{4-Cyclobutyl-2-fluoro-3-[3-methyl- 4- (methylsulfonyl)phenoxy]phenyl} pyrazin-2-amine

127 5-(4-cyclobutyl-2-fluoro-3-(4- (methylsulfonyl)-2- (trifluoromethyl)phenoxy)phenyl) pyrazin-2-amine

128 5-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyridin-3- yl]oxy}phenyl)pyrazin-2-amine

129 5-{4-Cyclobutyl-2-fluoro-3-[(3- methoxypyridin-2- yl)oxy]phenyl}pyrazin-2-amine

130 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 2-amine

131 5-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethyl)pyrimidin-2- yl]oxy}phenyl)pyrazin-2-amine

132 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-5- (methylsulfonyl)benzonitrile

133 5-{4-Cyclobutyl-2-fluoro-3-[4- (methylsulfonyl)-3- (trifluoromethyl)phenoxy]phenyl} pyrazin-2-amine

134 5-{4-Cyclobutyl-2-fluoro-3-[(2- methylpyrimidin-4- yl)oxy]phenyl}pyrazin-2-amine

135 5-(4-Cyclobutyl-2-fluoro-3-{[2-(1- methylethy)pyrimidin-4- yl]oxy}phenyl)pyrazin-2-amine

136 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 4-amine

137 5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

138 5-{3-[(6-Azetidin-1-ylpyrimidin-4- yl)oxy]-4-cyclobutyl-2- fluorophenyl}pyrazin-2-amine trifluoroacetate salt

139 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-N,N- dimethyl-2-(trifluoromethy)pyrimidin- 4-amine

140 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-2- methylpyrimidin-4-amine trifluoroacetate salt

141 5-{4-Cyclobutyl-3-[(6- cyclopropylpyrimidin-4-yl)oxy]-2- fluorophenyl}pyrazin-2-amine

142 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-6- (methoxymethyl)pyrimidin-2-amine

143 4-[3-(5-Aminopyrazin-2-yl)-6- cycloloutyl-2-fluorophenoxy]-6- chloropyrlmidin-2-amine

144 5-{4-Cyclobutyl-2-fluoro-3-[(2- phenylpyrimidin-4- yl)oxy]phenyl}pyrazin-2-amine

145 5-{4-Cyclobutyl-2-fluoro-3-[(6- phenylpyrimidin-4- yl)oxy]phenyl}pyrazin-2-amine

146 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-2- benzylpyrimidin-4-amine

147 5-(4-Cyclobutyl-2-fluoro-3-{[6-(1- methylethyl)pyrimidin-4- yl]oxy}phenyl)pyrazin-2-amine

148 3-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-1-methyl- 5-(trifluoromethyl)-1H-pyrazole-4- carbonitrile

149 tert-Butyl [2-({2-[3-(5-aminopyrazin-2- yl)-6-cyclobutyl-2- fluorophenoxy]pyrimidin-4- yl}amino)ethyl]carbamate

150 N-{4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 2-yl}ethane-1,2-diamine

151 Methyl 2-[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]pyrimidine-4- carboxylate trifluoroacetate salt

152 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]pyrimidine-4-carboxylic acid

153 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]benzoic acid

154 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine- 3-carboxylic acid

155 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]benzamide

156 N′-{4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 2-yl}-N,N-dimethylethane-1,2-diamine hydrochloride

157 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]pyrimidine-4- carboxamide

158 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 5-amine

159 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)pyrimidin-2-amine

E 3-(2-Aminopyrimidin-5-yl)-6- cyclobutyl-2-fluorophenol

160 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin- 2-yloxy)phenyl]pyrimidin-2-amine

161 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrimidin-2- amine

162 4-[3-(2-Aminopyrimn-5-yl)-6- cyclobutyl-2-fluorophenoxy]-6- (methoxymethyl)pyrimidin-2-amine

163 5-{4-Cyclobutyl-2-fluoro-3-[(4- methylpyrimidin-2- yl)oxy]phenyl}pyrimidin-2-amine

164 5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrimidin-2- amine

165 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1- methylethyl)pyrimidin-2- yl]oxy}phenyl)pyrimidin-2-amine

166 4-[3-(2-Aminopyrimidin-5-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 2-amine

167 5-{4-Cyclobutyl-3-[(4,6- dimethylpyrimidin-2-yl)oxy]-2- fluorophenyl}pynmidin-2-amine

168 4-(3-(2-aminopyrimidin-5-yl)-6- cyclobutyl-2-fluorophenoxy)-6- isopropylpyrimidin-2-amine

169 2-[3-(2-Aminopyrimidin-5-yl)-6- cyclobutyl-2- fluorophenoxy]pyrimidine-4- carboxamide

170 5-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4- yl)oxy)phenyl)pyrimidin-2-amine trifluoroacetate salt

171 6-[3-(2-Aminopyrimidin-5-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin- 4-ol trifluoroacetate

172 6-Amino-3-(4-cyclobutyl-2-fluoro-3- methoxyphenyl)pyrazine-2- carbonitrile

173 6-Amino-3-(4-cyclobutyl-2-fluoro-3- hydroxyphenyl)pyrazine-2-carbonitrile

174 3-{[3-(5-Amine-3-cyanopyrazin-2-yl)- 6-cyclobutyl-2- fluorophenoxy]methyl}benzoic acid

175 2-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-5H-pyrrolo[2,3- b]pyrazine

F 6-Cyclobutyl-2-fluoro-3-(5H- pyrrolo[2,3-b]pyrazin-2-yl)phenol

176 2-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethyl)benzyl]oxy}phenyl)- 5H-pyrrolo[2,3-b]pyrazine trifluoroacetate salt

177 2-[3-(Benzyloxy)-4-cyclobutyl-2- fluorophenyl]-5H-pyrrolo[2,3- b]pyrazine

178 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)pyridin-2-amine hydrochloride salt

179 5-(4-Cyclobutyl-2-fluoro-3- hydroxyphenyl)pyridin-2-amine

180 5-Methyl-4-((3-(6-aminopyridin-3-yl)- 6-cyclobutyl-2- fluorophenoxy)methyl)benzoate

181 4-((3-(6-Aminopyridin-3-yl)-6- cyclobutyl-2- fluorophenoxy)methyl)benzoic acid

182 5-(4-cyclobutyl-2-fluoro-3- methoxyphenyl)-1H-imidazo[4,5- b]pyrazine

183 6-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-3H-imidazo[4,5- b]pyridine

184 7-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine

185 6-Cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenol

186 7-[3-(Benzyloxy)-4-cyclobutyl-2- fluorophenyl]-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine

187 3-{[6-Cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]-methyl}-benzonitrile

188 7-(4-Cyclobutyl-2-fluoro-3-{[3- (methylsulfonyl)-benzyl]oxy}phenyl)- 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine

189 7-(4-Cyclobutyl-2-fluoro-3-{[4- (methylsulfonyl)-benzyl]-oxy}-phenyl)- 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine

190 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]-methyl}-benzonitrile

191 7-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethyl)benzyl]oxy}phenyl)- 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine

192 3-{[6-Cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]-methyl}-benzamide

193 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]-methyl}-benzamide

194 7-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyridin-2- yl]oxy}phenyl)-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine

195 (4-{[6-Cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}phenyl)acetic acid

196 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}benzoic acid

197 3-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-7H-pyrrolo[2,3- c]pyridazine

198 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine

199 6-Cyclobutyl-3-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-5-yl)-2- fluorophenol

G 3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2- fluorophenol

200 5-(4-tert-Butyl-3-{[tert- butyl(dimethyl)silyl]oxy}-2- fluorophenyl)pyrazin-2-amine

201 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl]pyrazin-2-amine

202 6-[3-(5-Aminopyrazin-2-yl)-6-tert- butyl-2-fluorophenoxy]pyrimidin-4- amine

203 2-[3-(5-Aminopyrazin-2-yl)-6-tert- butyl-2-fluorophenoxy]pyrimidin-4- amine

204 5-{4-tert-Butyl-2-fluoro-3-[(6- methoxypyrimidin-4- yl)oxy]phenyl}pyrazin-2-amine

205 5-(4-tert-Butyl-2-fluoro-3- methoxyphenyl)pyrazin-2-amine

H 3-(2-Aminopyrimidin-5-yl)-6-tert-butyl- 2-fluorophenol

206 5-(4-tert-Butyl-3-{[tert- butyl(dimethyl)silyl]oxy}-2- fluorophenyl)pyrimidin-2-amine

207 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl]pyrimidin-2-amine

208 5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4- tert-butyl-2-fluorophenyl}pyrimidin-2- amine

209 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4- tert-butyl-2-fluorophenyl}pyrimidin-2- amine

210 5-(4-Bromo-2-fluoro-3- methoxyphenyl)pyrazin-2-amine

211 5-(4-Cyclopentyl-2-fluoro-3- methoxyphenyl)pyrazin-2-amine

212 5-[3-(Benzyloxy)-4-cyclopentyl-2- fluorophenyl]pyrazin-2-amine

213 5-[4-Cyclopentyl-2-fluoro-3-(1- methylethoxy)phenyl]pyrazin-2-amine

214 2-[3-(Benzyloxy)-4-cyclopentyl-2- fluorophenyl]-5H-pyrrolo[2,3- b]pyrazine

215 5-[3-(Benzyloxy)-4-tert- butylphenyl]pyrazin-2-amine

216 5-[3-(Benzyloxy)-4-chloro-2- fluorophenyl]pyrazin-2-amine

217 5-[3-(Benzyloxy)-4- cyclobutylphenyl]pyrazin-2-amine

218 3-amino-6-(4-cyclobutyl-2-fluoro-3- methoxyphenyl)pyrazine-2- carbonitrile

219 6-(4-cyclobutyl-2-fluoro-3- methoxyphenyl)pyridazin-3-amine

220 6-cyclobutyl-2-fluoro-3-(1H- pyrrolo[2,3-b]pyridin-5-yl)phenol

221 6-cyclobutyl-2-fluoro-3-(7H- pyrrolo[2,3-c]pyridazin-3-yl)phenol

222 3-amino-6-(4-cyclobutyl-2-fluoro-3- hydroxyphenyl)pyrazine-2-carbonitrile

223 3-(6-aminopyridazin-3-yl)-6- cyclobutyl-2-fluorophenol

224 5,5′-((pyrimidine-2,4- diylbis(oxy))bis(4-cyclobutyl-2-fluoro- 3,1-phenylene))bis(pyrazin-2-amine

225 7-(4-cyclobutyl-2-fluoro-3-(pyrimidin- 2-yloxy)phenyl)-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine

226 2-(6-cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy)pyrimidin-4-amine

227 7-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4-yl)oxy)phenyl)- 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine

228 5-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4-yl)oxy)phenyl)- 1H-pyrrolo[2,3-b]pyridine

229 2-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4-yl)oxy)phenyl)- 5H-pyrrolo[2,3-b]pyrazine

230 2-(4-cyclobutyl-2-fluoro-3-(pyrimidin- 2-yloxy)pheny)-5H-pyrrolo[2,3- b]pyrazine

231 6-(4-cyclobutyl-2-fluoro-3-(pyrimidin- 2-yloxy)phenyl)pyridazin-3-amine

232 6-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4- yl)oxy)phenyl)pyridazin-3-amine

233 6-(3-(6-aminopyridazin-3-yl)-6- cyclobutyl-2-fluorophenoxy)pyrimidin- 4-ol

234 4-(3-(5-Amnopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy)pyrimidine-2- carbonitrile

235 6-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-N,N,2- trimethylpyrimidin-4-amine

236 4-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-N,N,6- trimethylpyrimidin-2-amine

237 6-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-N,N- dimethylpyrimidin-4-amine

238 Ethyl 5-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-1-methyl- 3-(trifluoromethyl)-1H-pyrazole-4- carboxylate

239 5-(4-cyclobutyl-2-fluoro-3-((5- (methylsulfonyl)pyridin-2- yl)oxy)phenyl)pyrazin-2-amine

240 4-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-6-(tert- butyl)pyrimidin-2-amine

241 5-(3-((4-(1,5-dioxa-9- azaspiro[5.5]undecan-9-yl)pyrimidin- 2-yl)oxy)-4-cyclobutyl-2- fluorophenyl)pyrazin-2-amine

242 4-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-6- isobutylpyrimidin-2-amine

I 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-1H-pyrrolo[2,3- b]pyridine

243 N-(2-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-ethyl)- methane-sulfonamide

244 5-(4-Cyclobutyl-2-fluoro-3-(2- morpholinoethoxy)phenyl)pyrazin-2- amine

245 Ethyl 4-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)butanoate

246 tert-Butyl 3-((3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2- fluorophenoxy)methyl)azetidine-1- carboxylate

247 tert-Butyl 3-((3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2- fluorophenoxy)methyl)pyrrolidine-1- carboxylate

248 tert-Butyl 2-((3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2- fluorophenoxy)methyl)pyrrolidine-1- carboxylate

249 tert-Butyl 3-((3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2- fluorophenoxy)methyl)piperidine-1- carboxylate

250 2-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)ethanol

251 4-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)butanoic acid

252 5-(4-Cyclobutyl-2-fluoro-3- ((tetrahydrofuran-2- yl)methoxy)phenyl)pyrazin-2-amine

253 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3- (isobutylamino)propan-2-ol

254 racemic 3-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)propane- 1,2-diol

255 racemic 1-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3- morpholinopropan-2-ol

256 racemic 4-(3-(3-(5-Aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)thiomorpholine 1,1- dioxide

257 5-(4-Cyclobutyl-2-fluoro-3-(pyridazin- 4-yloxy)phenyl)pyrazin-2-amine

258 3-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)pyrazin-2- amine

259 5-(4-Cyclobutyl-2-fluoro-3-(pyrazin-2- yloxy)phenyl)pyrazin-2-amine

260 5-(4-Cyclobutyl-2-fluoro-3-(pyrimidin- 4-yloxy)phenyl)pyrazin-2-amine

261 4-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-N- isobutylpyrimidin-2-amine trifluoroacetic acid salt

262 Methyl 2-{[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}- 1,3-benzoxazole-5-carboxylate

263 Methyl 3-({[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]acetyl}amino)-4- hydroxybenzoate

264 5-[4-Cyclobutyl-2-fluoro-3-(tetrahydro- 2H-pyran-4- ylmethoxy)phenyl]pyrazin-2-amine

265 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3- (methylsulfonyl)benzonitrile

266 5-{3-[2,4- Bis(trifluoromethyl)phenoxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

267 5-{4-Cyclobutyl-3-[3- (dimethylamino)propoxy]-2- fluorophenyl}pyrazin-2-amine

268 5-{4-Cyclobutyl-3-[2- (dimethylamino)ethoxy]-2- fluorophenyl}pyrazin-2-amine

269 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-N,6- dimethylpyrimidin-2-amine

270 2-[6-Cyclobutyl-2-fluoro-3-(7H- pyrrolo[2,3-c]pyridazin-3- yl)phenoxy]pyrimidin-4-amine

271 5-{4-Cyclobutyl-3-[(6,7- difluoroquinoxalin-2-yl)oxy]-2- fluorophenyl}pyrazin-2-amine

272 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]quinazolin-4-amine

273 2-Amino-5-[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]pyrimidine-4- carbonitrile

274 Methyl 2-{[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}- 1,3-benzoxazole-5-carboxylate

275 Methyl 3-({[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]acetyl}amino)-4- hydroxybenzoate

276 [3-(5-Aminopyrazin-2-yl)-6-cyclobutyl- 2-fluorophenoxy]acetonitrile

277 5-[4-Cyclobutyl-2-fluoro-3-(pyridazin- 3-yloxy)phenyl]pyrazin-2-amine

278 5-[4-Cyclopropyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl]pyrazin-2- amine

279 2-[3-(5-Aminopyrazin-2-yl)-6- cyclopropyl-2- fluorophenoxy]pyrimidin-4-amine

280 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl- 1H-imidazol-2- yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

281 Methyl 2-{[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}- 1,3-oxazole-4-carboxylate trifluoroacetic acid salt

282 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}- 1,3-oxazole-4-carboxylic acid trifluoroacetic acid salt

283 5-[3-(1,3-Benzothiazol-2-ylmethoxy)- 4-cyclobutyl-2-fluorophenyl]pyrazin-2- amine trifluoroacetic acid salt

284 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl- 1H-imidazol-4- yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

285 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl- 1H-imidazol-5- yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

286 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}pyridine-3- carbonitrile trifluoroacetic acid salt

287 5-{4-Cyclobutyl-2-fluoro-3-[(2-methyl- 1,3-thiazol-4- yl)methoxyl]phenyl}pyrazin-2-amine trifluoroacetic acid salt

288 5-[4-Cyclobutyl-2-fluoro-3-(pyridazin- 3-ylmethoxy)phenyl]pyrazin-2-amine trifluoroacetic acid salt

289 5-{3-[(5-Chloropyridin-2-yl)methoxy]- 4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine trifluoroacetic acid salt

290 5-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}pyridine-2- carbonitrile trifluoroacetic acid salt

291 5-{4-Cyclobutyl-2-fluoro-3-[(5- methylisoxazol-3- yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

292 6-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}pyridine-2- carbonitrile trifluoroacetic acid salt

293 2-{2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]ethyl}-1H- isoindole-1,3(2H)-dione

294 5-[3-(2-Aminoethoxy)-4-cyclobutyl-2- fluorophenyl]pyrazin-2-amine

295 5-{4-Cyclobutyl-2-fluoro-3-[2-(pyrazin- 2-ylamino)ethoxy]phenyl}pyrazin-2- amine trifluoroacetic acid salt

296 N-{2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]ethyl}pyrimidin-2- amine trifluoroacetic acid salt

297 N-{2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]ethyl}pyrimidin-4- amine

298 5-[4-Cyclobutyl-2-fluoro-3-(piperidin- 4-ylmethoxy)phenyl]pyrazin-2-amine hydrogen chloride salt

299 racemic 5-[4-Cyclobutyl-2-fluoro-3- (piperidin-3- ylmethoxy)phenyl]pyrazin-2-amine

300 racemic 5-[4-Cyclobutyl-2-fluoro-3- (pyrrolidin-3- ylmethoxy)phenyl]pyrazin-2-amine

301 5-[3-(Azetidin-3-ylmethoxy)-4- cyclobutyl-2-fluorophenyl]pyrazin-2- amine

302 racemic 5-[4-Cyclobutyl-2-fluoro-3- (pyrrolidin-2- ylmethoxy)phenyl]pyrazin-2-amine

303 racemic 5 1-[3-(5-Aminopyrazin-2-yl)- 6-cyclobutyl-2-fluorophenoxy]-3- piperidin-1-ylpropan-2-ol

304 racemic 1-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3- (methylamino)propan-2-ol

305 racemic 1-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3-[(1- methylethyl)amino]propan-2-ol

306 racemic 1-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3- pyrrolidin-1-ylpropan-2-ol

307 racemic 1-[3-(5-Aminopyrazin-2-yl)-6- cycloloutyl-2-fluorophenoxy]-3- (dimethylamino)propan-2-ol

308 diastereomeric mixture 1-{3-[3-(5- Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]-2- hydroxypropyl}pyrrolidin-3-ol

309 racemic 1-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3- piperazin-1-ylpropan-2-ol

310 racemic 1-{3-[3-(5-Aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy]-2- hydroxypropyl}pyrimidin-2(1H)-one

311 racemic 1-{3-[3-(5-Aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy]-2- hydroxypropyl}-1,3-dihydro-2H- benzimidazol-2-one

312 racemic 1-{3-[3-(5-Aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy]-2- hydroxypropyl}imidazolidin-2-one

313 2′-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-5,5′- bipyrimidin-2-amine

314 5-[2-Fluoro-4-methyl-3-(pyrimidin-2- yloxy)phenyl]pyrazin-2-amine

315 2-[3-(5-Aminopyrazin-2-yl)-2-fluoro-6- methylphenoxy]pyrimidin-4-amine

316 5-[4-Ethyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl]pyrazin-2-amine

317 2-[3-(5-Aminopyrazin-2-yl)-6-ethyl-2- fluorophenoxy]pyrimidin-4-amine

318 5-[2-Fluoro-4-(1-methylethyl)-3- (pyrimidin-2-yloxy)phenyl]pyrazin-2- amine

319 5-[2-Fluoro-4-propyl-3-(pyrimidin-2- yloxy)phenyl]pyrazin-2-amine

320 5-(4-Cyclohexyl-2-fluoro-3-(pyrimidin- 2-yloxy)phenyl)pyrazin-2-amine

321 5-(4-(Cyclohexylmethyl)-2-fluoro-3- (pyrimidin-2-yloxy)phenyl)pyrazin-2- amine

322 5-(2-Fluoro-4-isopentyl-3-(pyrimidin- 2-yloxy)phenyl)pyrazin-2-amine

323 5-(2-Fluoro-4-isobutyl-3-(pyrimidin-2- yloxy)phenyl)pyrazin-2-amine

324 5-(2-Fluoro-4-neopentyl-3-(pyrimidin- 2-yloxy)pheny)pyrazin-2-amine

325 2-(3-(5-Aminopyrazin-2-yl)-6- cyclohexyl-2-fluorophenoxy)pyrimidin- 4-amine

326 2-(3-(5-Aminopyrazin-2-yl)-6- (cyclohexylmethyl)-2- fluorophenoxy)pyrimidin-4-amine

327 2-(3-(5-Aminopyrazin-2-yl)-2-fluoro-6- isopentylphenoxy)pyrimidin-4-amine

328 2-(3-(5-Aminopyrazin-2-yl)-2-fluoro-6- isobutylphenoxy)pyrimidin-4-amine

329 5-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy)pyrimidine-2- carboxamide

330 5-(4-Cyclobutyl-2-fluoro-3- (thiazolo[4,5-b]pyridin-2- yloxy)phenyl)pyrazin-2-amine

331 5-(4-Cyclobutyl-2-fluoro-3- ((5-methylthieno[2,3-d]pyrimidin-4- yl)oxy)phenyl)pyrazin-2-amine

332 N⁴-(2-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy)ethyl)pyrimidine-2,4- diamine

333 3-(5-Aminopyrazin-2-yl)-6-ethyl-2- fluorophenol

334 5-[4-Cyclopentyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl]pyrimidin-2- amine

335 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4- cyclopentyl-2-fluorophenyl}pyrimidin- 2-amine

336 2-[3-(5-Aminopyrazin-2-yl)-6- cyclopentyl-2- fluorophenoxy]pyrimidin-4-amine

337 5-[4-Cyclopentyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl]pyrazin-2- amine

338 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridazin- 3-amine

339 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin- 2-ylmethoxy)phenyl]pyrazin-2-amine

340 5-{3-[(4-Bromobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

341 5-(4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]methyl}phenyl)pyrimidin- 2-amine

342 5-(4-Cyclobutyl-2-fluoro-3-{[4′- (trifluoromethyl)biphenyl-4- yl]methoxy}phenyl)pyrazin-2-amine

343 5-[4-Cyclohexyl-2-fluoro-3-(pyrimidin- 2-yloxy)phenyl]pyrimidin-2-amine

344 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4- cyclohexyl-2-fluorophenyl}pyrimidin- 2-amine

345 3-(5-Aminopyrazin-2-yl)-6-cyclohexyl- 2-fluorophenol

346 3-(5-Aminopyrazin-2-yl)-6- (cyclohexylmethyl)-2-fluorophenol

347 5-{3-[(2-Aminopyridin-4-yl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

348 5-{3-[(6-Aminopyrazin-2-yl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2- amine

349 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin- 5-yloxy)phenyl]pyrazin-2-amine

350 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridazin- 4-amine

351 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl]-1H-pyrrolo[2,3- b]pyridine

C) Synthesis

The invention provides methods of making the disclosed compounds according to traditional organic synthetic methods as well as matrix or combinatorial synthetic methods. Scheme A described suggested synthetic routes. Using the schemes, the guidelines below, and the examples, a person of skill in the art may develop analogous or similar methods for a given compound that is within the invention. These methods are representative of the synthetic schemes, but are not to be construed as limiting the scope of the invention.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or as individual enantiomers or diasteromers by either stereospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all stereoisomers, racemic mixtures, diastereomers, geometric isomers, and enantiomers thereof are encompassed within the scope of the present invention.

Representative compounds of the present invention can be synthesized in accordance with the general synthetic schemes described below and are illustrated more particularly in the specific synthetic examples that follow. The general schemes are offered by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions expressed. The methods for preparing the various starting materials used in the schemes and examples are well within the skill of persons versed in the art. No attempt has been made to optimize the yields obtained in any of the example reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents.

General: ¹H and ¹³C NMR spectra were measured on a Bruker AC-300 (300 MHz) spectrometer using tetramethylsilane and the deuterated solvent respectively as internal standards. Elemental analyses were obtained by Quantitative Technologies Inc. (Whitehouse, N.J.) and the results were within 0.4% of the calculated values unless otherwise mentioned. Melting points were determined in open capillary tubes with a Mel-Temp II apparatus (Laboratory Devices Inc.) and were uncorrected. Electrospray mass spectra (MS-ESI) were recorded in the positive mode on a Hewlett Packard 59987A spectrometer. High resolution mass spectra (HRMS) were obtained on a Micromass Autospec. E spectrometer by fast atom bombardment (FAB) technique.

Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Examples of the described synthetic routes include Scheme A, Intermediates A-N, Examples 1-351 and prophetic Examples 1-36. Compounds analogous to the target compounds of these examples can be made according to similar routes. The disclosed compounds are useful as pharmaceutical agents as described herein.

Abbreviations or acronyms used herein include:

Abbreviation Meaning BOC/boc tert-butyloxycarbonyl BOP benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate CDCl₃ deuterated chloroform Cpd compound DCE dichloroethane DCM dichloromethane DMAP dimethylaminopyridine DIPEA diisopropyl ethyl amine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPBS Dulbecco's phosphate buffered saline EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ESI Electrospray Ionization Et₃N or TEA triethylamine Et₂O diethyl ether EtOAc ethyl acetate h/hr/hrs hour(s) HOBT 1-hydroxybenzotriazole hydrate HBTU O-benzotriazol-1-yloxy-N,N,N′,N′-tetramethyluronium hexafluorophosphate HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate LG Leaving group LiOH lithium hydroxide MeCN Acetonitrile MeOH methanol min minute(s) MS mass spectroscopy NMR nuclear magnetic resonance spectroscopy OTf Triflate PG protecting group RT/rt room temperature TBME tert-Butyl-methyl ether TFA trifluoro acetic acid THF tetrahydrofuran TLC thin layer chromatography Tos p-toluenesulfonyl MgSO₄ Magnesium sulfate EtOH Ethanol BBr₃ Boron tribromide

General Guidance

Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated more particularly in the schemes that follow. Since the schemes are illustrations, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art. The substituents for compounds of Formula (I) or a form thereof, represented in the schemes below, are as previously defined herein.

Unless otherwise specified, reaction solutions were stirred at room temperature under a N_(2(g)) or Ar_((g)) atmosphere. When solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure, when solutions were dried, they are typically dried over a drying agent such as magnesium sulfate (MgSO₄) or sodium sulfate (Na₂SO₄).

Normal phase flash column chromatography (FCC) was performed on silica gel with RediSep® silica gel columns using ethyl acetate (EtOAc)/hexanes, CH₂Cl₂/MeOH, CH₂Cl₂/10% 2 N NH₃ in MeOH, CH₂Cl₂/i-PrOH, and the like as eluent, unless otherwise indicated.

Reverse phase high performance liquid chromatography (HPLC) was performed under the following conditions: 1) Instrument, Shimadzu; Column, Waters XBridge C18 μM (250×50 mm), Phenomenex Gemini column 5 μm C18 (150×21.2 mm) or Waters Xterra RP18 OBD 5 μm (100×30 mm); Gradient, 95:5 to 0:100 water (0.05% trifluoroacetic acid (TFA))/CH₃CN (0.05% TFA); Flow rate, 30-80 mL/min; Detection, UV at λ=220-254 nM; 2) Instrument, Gilson; Column, Phenomenex LUNA column 5 μm C18 (250×50 mm) or Waters XBridge Prep C18 OBD 5 μm (30×150 mm); Gradient, 95:5 to 0:100 water (0.05% TFA)/CH₃CN (0.05% TFA); Flow rate, 30-80 mL/min; Detection, UV at λ=220-254 nM; 3) Instrument, Gilson/Shimadzu: Column, Inertsil ODS-3 column (30×100 mm) or Inertsil ODS-3 (30×50 mm, 5 μm); Gradient, water-acetonitrile with both phases with 0.05% by volume trifluoroacetic acid; 1 min hold at 5% ACN, then 6 min gradient to 99% ACN followed by a hold at that concentration for 3 min. Flow rate, 80 ml/min; heated column at 46° Celsius with detection of UV light at λ=254 nm; and 4) Instrument, Dionex: UVD 170U Diode array detector and ThermoFinnegan Surveyor MSQ plus mass spectrometer for data collection. Waters XBridge C18 5 μM OBD 50×100 mm prep column. All runs utilized water acetonitrile with 20 mM NH₄OH added to the aqueous phase and a flow rate for all gradients was 80 mL/min using four possible gradients: 1) 5-60% MeCN over 12 min, then ramped to 100% MeCN and held for 6.3 min; 2) 30-70% MeCN over 12 min, then ramped to 100% MeCN and held for 6.3 min; 3) 50-80% MeCN over 12 min, then ramped to 100% MeCN and held for 6.3 min; and 4) 60-100% MeCN over 12 min, and then held for 6.3 min. The total run time for all gradient systems was 18.5 min.

Instances where solutions were filtered through a syringe filter, Pall 0.45 μM GHP membrane 13 mm and 25 mm diameter syringe filters were used.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄ 2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gel plates. Preparative thin-layer chromatography was performed using EM Science silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a 20 cm×4 cm concentrating zone. Microwave reactions were carried out in either a CEM Discover® or a Biotage Initiator™ or Optimizer™ microwave at specified temperatures. Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated mass corresponds to the exact mass. NMR spectra were obtained on either a Bruker model DPX400 (400 MHz), DPX500 (500 MHz), DRX600 (600 MHz) spectrometer. The format of the ¹H NMR data below is: chemical shift in ppm down field of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

Hydrochloride salts were obtained by treating the corresponding free bases with HCl (4 N in dioxane, 2 M in Et₂O, or 1.25 N in MeOH) at room temperature with mixtures and then either concentrated to obtain the HCl salt, or the resulting solid being isolated by filtration. Trifluoroacetic acid salts were obtained by purification of the crude reaction product by preparative reverse phase HPLC, whereby the final products were isolated as either mono-, di- or tri trifluoroacetic acid salts.

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoft Corp., Cambridge, Mass.) or ACD/Name Version 10.01 (Advanced Chemistry).

The compounds of Formula (I), wherein ring A, L, R₁, R₂, R₃, R₄ and R₅ are defined as in Formula (I), may be synthesized as outlined by the general synthetic route illustrated in Scheme A.

Referring to Scheme A, compounds of Formulae (XIII) can be prepared from appropriately substituted phenols (X) wherein the phenol (—OP) is protected as either an alkyl or alkyl and aryl silyl ether. Protected phenols, as the methyl ether, can be prepared by known methods or can be obtained commercially. Compounds (X), where W is a hydrogen and X is either bromo or chloro, can be converted to the corresponding boronic acid (XIV) via directed ortho-metallation (DOM) using bases such as LDA, and lithium tetramethyl piperidide (LTMP) (either made in situ or obtained from commercial sources) and triisopropyl borate in solvents such as THF, DME, ether and mixtures thereof at temperatures ranging from ⁻78-0° Celsius. In compounds of formulae (XIV) where X is bromo or chloro and Z is fluoro or hydrogen, compound (XV) can be obtained via sequential Pd cross-coupling reactions to install Ar¹ followed by Y. Preferred solvents for cross-coupling reactions were conducted in a solvent, such as DME, DMSO, DMF, DMA, dioxane, THF, EtOH or toluene, or mixtures of the aforementioned solvents, with or without added water in the presence of a base, such as Na₂CO₃, K₂CO₃, KOAc, KH₂PO₄, K₂HPO₄, or K₃PO₄, using a palladium catalysts, such as Pd(dppf)Cl₂.CH₂Cl₂, palladium(II) trifluoroacetate and Ph₃P, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]-palladium(II), 1,1′-bis[di-t-butylphosphino)ferrocene]-palladium(II) chloride with temperatures ranging from room temperature to 120° Celsius.

Additionally, compounds of formulae (XI) where W is hydrogen, Z is either H or fluoro, and Y is alkyl or cycloalkyl can be formed from compound (X), where X is bromo, via metal halogen exchange using alkyllithium or alkylmagnesium halide reagents, such as nBuLi or i-PrMgCl, in solvents such as di-ethyl ether or THF at temperatures ranging from ⁻78° Celsius to room temperature followed by treatment with an electrophile. In those instances wherein a ketone is used as the electrophile, such as cyclobutanone or cyclopentanone, reduction of the resulting hydroxyl group can be achieved using known methods such as Et₃SiH in DCM in the presence of TFA. Alternatively, compound of formulae (XI) can be obtained through use of a palladium catalyst, such as palladium(II) acetate, with an added ligand, such as 2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl, to couple (X) to an alkyl or arylzinc reagent, such as cyclobutylzinc bromide, in a solvent, such as THF, at temperatures ranging from rt to 100° Celsius. Compound of formulae (XI) can be further elaborated to those of formulae (XII), using previously described methods such as DOM, borylation, and Pd mediated cross-coupling. Compounds of formulae (X) in which X is alkyl, aryl or heteroaryl can be converted to compounds of formulae (XII) or (XV) through DOM, borylation, and Pd mediated cross-coupling using methods.

Compounds of formulae (XIII) can be obtained from those of formulae (XII) or (XV) by first removing the silyl protecting group using a fluoride source, such as TBAF or CsF in solvents such as THF, followed by subjecting the resultant phenol to S_(N)2 or S_(N)Ar reaction conditions in the presence of a suitable electrophile and solvents such as DMF, DMSO and DMA in the presence of bases such as K₂CO₃, Cs₂CO₃. Na₂CO₃, and K₂PO₄ at temperatures ranging from 0-140° Celsius. Alternatively, compounds of formulae (XIII) can prepared via intermediates of formulae (XII) and (XV) wherein P is a methyl group. Removal of the methyl group can be achieved using known methods.

Preferred methods for removal of methyl ethers include BBr₃ in DCM at temperatures ranging from 78° Celsius to 0° Celsius. Compounds of formulae (XIII) are formed using suitable electrophiles such as various alkyl, aryl, and heteroaryl halides in the presence of bases such as K₂CO₃ or Cs₂CO₃ with or without the presence of cation chelation agents, such as 18-crown-6, in solvents such as DMSO, DMA, ACN, DMF and mixtures thereof at temperatures ranging from 0-140° Celsius using either conventional or microwave heating.

EXAMPLES

The following examples are offered by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions expressed.

Intermediate A

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine Step A: 1-(3-Fluoro-2-methoxyphenyl)cyclobutanol

To a 500 mL round-bottomed flask were added a stir bar, 2-bromo-6-fluoroanisol (11.03 g, 53.8 mmol) and dry THF (215 mL). The flask was purged with nitrogen and cooled to 0° Celsius before adding 2.0 M i-PrMgCl in THF (60 mL, 120 mmol) over the course of 3 min. The resultant mixture was stirred for 2 h before adding cyclobutanone (5.0 mL, 67 mmol). The resultant mixture was stirred for 0.5 hour before diluting with Et₂O (500 mL) and washing with saturated NH₄Cl followed by brine. The organic layer was isolated, dried over MgSO₄, filtered and concentrated to dryness to give a pale-yellow oil. Subjecting the residue to FCC yielded 1-(3-fluoro-2-methoxyphenyl)cyclobutanol as a pale-yellow oil (5.18 g, 49%). ¹H NMR (600 MHz, CDCl₃) δ 7.07-7.03 (m, 1H), 7.03-6.98 (m, 1H), 6.98-6.94 (m, 1H), 3.99 (d, J=2.4, 3H), 3.39 (s, 1H), 2.57-2.45 (m, 2H), 2.41-2.31 (m, 2H), 2.17-2.05 (m, 1H), 1.75-1.65 (m, 1H).

Step B: 1-Cyclobutyl-3-fluoro-2-methoxybenzene

To a 500 mL round-bottomed flask were added a stir bar, 1-(3-fluoro-2-methoxyphenyl)cyclobutanol (5.21 g, 26.6 mmol), dry DCM (250 mL), Et₃SiH (39.0 mL, 244 mmol) and TFA (20 mL, 260 mmol). The resultant mixture was stirred at rt for 22 h before concentrating to dryness and subjecting the residue to FCC to give 1-cyclobutyl-3-fluoro-2-methoxybenzene as a pale-yellow oil (3.78 g, 79%). ¹H NMR (600 MHz, CDCl₃) δ 7.03-6.99 (m, 1H), 6.99-6.95 (m, 1H), 6.91 (m, 1H), 3.86 (d, J=1.6, 3H), 3.83-3.72 (m, 1H), 2.39-2.28 (m, 2H), 2.19-2.07 (m, 2H), 2.07-1.98 (m, 1H), 1.89-1.80 (m, 1H).

Step C: (4-Cyclobutyl-2-fluoro-3-methoxyphenyl)boronic Acid

To a 500 mL round-bottomed flask were added a stir bar, dry THF (60 mL) and 2,2,6,6-tetramethylpiperidine (8.0 mL, 47 mmol). The flask was cooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (18.0 mL, 45 mmol) over 2 min. The resultant mixture was stirred for 5 min and then allowed to warm to 0° C. After 35 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)₃ (10.20 mL, 44 mmol) over 4 min. After 16 min, a solution consisting of 1-cyclobutyl-3-fluoro-2-methoxybenzene (7.24 g, 40.2 mmol) and dry THF (20.0 mL) was added over the course of 6 min and stirring continued for 3.5 h before adding HOAc (8 mL). The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL), the extract dried over MgSO₄, filtered and concentrated to dryness to give (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid as an off-white solid (8.08 g, 90%). The crude product was used directly in the next synthetic step.

Step D: 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

To a 1000 mL round-bottom flask were added a stir bar, 2-amino-5-bromopyrazine (19.95 g, 115.3 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (25.0 g, 112 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (5.92 g, 7.28 mmol) and K₂CO₃ (47.33 g, 343 mmol). The flask was flushed with nitrogen and then charged with sparged toluene (97 mL), sparged water (97 mL) and sparged DMF (61 mL). The reaction vessel was heated at 80° Celsius for 17 hours before cooling to room temperature. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was extracted with EtOAc (200 mL×3), the combined extracts dried over MgSO₄, filtered and concentrated to dryness. The residue was subjected to FCC to give the title compound (29.68 g). MS (ESI): mass calcd. for C₁₅H₁₆FN₃O, 273.13; m/z found, 274.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.32-8.26 (dd, J=2.5, 1.5, 1H), 8.02-7.96 (d, J=1.5, 1H), 7.54-7.47 (m, 1H), 7.20-7.14 (m, 1H), 6.65 (s, 2H), 3.87-3.79 (d, J=1.0, 3H), 3.79-3.68 (m, 1H), 2.34-2.24 (m, 2H), 2.17-2.06 (m, 2H), 2.06-1.94 (m, 1H), 1.87-1.76 (m, 1H).

Intermediate B

3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol Method 1: Step A: 1-(3-Fluoro-2-methoxyphenyl)cyclobutanol

To a 3-L round-bottom flask were added a stir bar, 2-bromo-6-fluoroanisol (75.00 g, 370 mmol) and dry THF (1460 mL). The flask was purged with nitrogen and cooled to 0° Celsius before adding 2.0 M i-PrMgCl in THF (408 mL, 916 mmol) over the course of 15 min. The resultant mixture was stirred for 2 hours before adding cyclobutanone (34 mL, 455 mmol). The resultant mixture was stirred for 0.5 hour before diluting with Et₂O (2.50 L) and washing with saturated NH₄Cl followed by brine. The organic layer was isolated, dried over MgSO₄, filtered and concentrated to dryness to give the crude product. Subjecting the residue to FCC gave the title compound (55.58 g). ¹H NMR (400 MHz, CDCl₃) δ 6.98-6.88 (m, 3H), 3.90-3.90 (s, 3H), 2.46-2.42 (m, 2H), 2.31-2.28 (m, 2H), 2.04 (m, 1H), 1.67-1.64 (m, 1H).

Step B: 1-Cyclobutyl-3-fluoro-2-methoxybenzene

To a 3-L round-bottom flask were added a stir bar, 1-(3-fluoro-2-methoxyphenyl)-cyclobutanol (80.17 g, 410 mmol), dry DCM (1231 mL), Et₃SiH (200 mL, 1.23 mol) and TFA (93 mL, 1.2 mmol). The resultant mixture was stirred at rt for 22 h before concentrating to dryness and subjecting the residue to FCC to give 1-cyclobutyl-3-fluoro-2-methoxybenzene as a pale-yellow oil (51.90 g, 70.5%). ¹HNMR (400 MHz, CDCl₃) δ 7.07-6.93 (m, 3H), 3.91 (s, 3H), 3.85-3.81 (m, 1H), 2.40-2.36 (m, 2H), 2.20-2.07 (m, 3H), 1.91-1.88 (m, 1H).

Step C: (4-Cyclobutyl-2-fluoro-3-methoxyphenyl)boronic Acid

To a 500 mL round-bottom flask were added a stir bar, dry THF (83 mL) and 2,2,6,6-tetramethylpiperidine (11 mL, 65 mmol). The flask was cooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (25 mL, 62.5 mmol) over 2 min. The resultant mixture was stirred for 5 min and then allowed to warm to 0° C. After 35 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)₃ (14 mL, 60 mmol) over 4 min. After 16 min, a solution consisting of 1-cyclobutyl-3-fluoro-2-methoxybenzene (10.0 g, 55.6 mmol) and dry THF (27 mL) was added over the course of 6 min and stirring continued for 3.5 hours before adding saturated NH₄Cl (200 mL). The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL×3), the combined extracts dried over MgSO₄, filtered and concentrated to dryness to give the crude product as an off-white solid. The crude product was subjected to FCC to give the title compound (7.21 g). ¹HNMR (400 MHz, CD₃OD): δ 7.11-7.07 (m, 2H), 3.38 (s, 3H), 3.82-3.80 (m, 1H), 2.37-2.33 (m, 2H), 2.19-2.11 (m, 3H), 2.09-1.90 (m, 1H).

Step D: 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

To a 1000 mL round-bottom flask were added a stir bar, 2-amino-5-bromopyrazine (19.95 g, 115.3 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (25.0 g, 112 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (5.92 g, 7.28 mmol) and K₂CO₃ (47.33 g, 343 mmol). The flask was flushed with nitrogen and then charged with sparged toluene (97 mL), sparged water (97 mL) and sparged DMF (61 mL). The reaction vessel was heated at 80° Celsius for 17 hours before cooling to room temperature. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was extracted with EtOAc (200 mL×3), the combined extracts dried over MgSO₄, filtered and concentrated to dryness. The residue was subjected to FCC to give the title compound (29.68 g). MS (ESI): mass calcd. for C₁₅H₁₆FN₃O, 273.13; m/z found, 273.9 [M+H]⁺.

Step E

To a 3 L round-bottom flask were added a stir bar, 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine (29.68 g, 121.0 mmol) and dry DCM (1190 mL). The flask was purged with nitrogen, stirred until homogeneous and cooled to −78° Celsius. Once cool, the flask was charged with 1.0 M BBr₃ in DCM (364 mL, 364 mmol). After 3 hours, the reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was then poured carefully into a flask containing ice (300 mL) and saturated NaHCO₃ resulting in the appearance of a tan ppt. The resultant mixture was subjected to vacuum filtration to give pure title compound as a tan solid (86%). ¹H NMR (400 MHz, CD₃OD), δ 8.29 (s, 1H), 8.04 (s, 1H), 7.21-7.17 (m, 1H), 7.08-7.05 (d, J=8.4, 1H), 3.87-3.78 (m, 1H), 2.40-2.34 (m, 2H), 2.23-2.12 (m, 2H), 2.10-2.01 (m, 1H), 1.91-1.85 (m, 1H).

Method 2: Step A: (2-Bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane

A 500-mL three-neck, round bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet, was charged with 2-bromo-6-fluorophenol (25 g, 130.9 mmol, 1.00 eq), DMF (252 mL, 0.52 M), imidazole (12.3 g, 181 mmol, 1.38 eq) and tertbutyldimethylsilyl chloride (19.7 g, 131 mmol, 1.00 eq). The mixture was heated at 60° Celsius for 3 hours. The reaction was cooled to room temperature and diluted with water. The aqueous phase was extracted with ethyl acetate and the resultant organic solution washed with water and brine and dried over sodium sulfate. The organic phase was concentrated to dryness and purified using FCC to provide (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane as a colorless oil (33 g, 82%).

Step B: (2-Cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane

A 1-L three-neck, round bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet was charged with (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (27.2 g, 89.1 mmol), THF (181.2 mL) and bis(tri-tert-butylphosphine)palladium (3.4 g, 6.68 mmol). Cyclobutylzinc bromide (267.2 mL, 134 mmol) was added and the reaction is heated at 45° Celsius for 22 hours. The reaction was cooled to room temperature and quenched with 1M HCl. The aqueous phase is extracted with MTBE and the combined organic extracts were washed with water, saturated aqueous thiourea, 1M HCl brine, dried over sodium sulfate and concentrated to dryness to provide (2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane as a light yellow oil (24.5 g, 98%). MS (EI): calcd. for C₁₆H₂₅FOSi, 280.5; m/z found 280.1 [M]. ¹H NMR (400 MHz, CDCl₃), δ 7.08-7.04 (m, 1H), 6.90-6.83 (m, 2H), 3.81 (tt, J=9.4, 7.8 Hz, 1H), 2.32 (dtd, J=10.3, 7.8, 2.4 Hz, 2H), 2.14-1.80 (m, 4H), 1.03 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H).

Step C: (3-((tert-Butyldimethylsilyl)oxy)-4-cyclobutyl-2-fluorophenyl)boronic Acid

A 100 mL three neck round-bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet, was charged with 2,2,6,6-tetramethylpiperidine (1.7 mL, 10 mmol) and THF (10 mL). The mixture was cooled to −78° Celsius and treated with 2.5 M n-BuLi (4.1 mL, 10 mmol). The resultant mixture was stirred for 5 min and then warmed up to 0° Celsius for 40 min. After 40 min the reaction mixture was cooled to −78° Celsius and treated with B(O-^(i)Pr)₃ (13.0 mL, 10.2 mmol) over the course of 10 min. After stirring for 20 min a solution of (2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane (1.8 g, 6.3 mmol) in THF (4 mL) was added over the course of 2 min. The reaction was stirred at −78° Celsius for 2 hours and then warmed to 0° Celsius. Acetic acid (3.6 mL, 64 mmol) is added and the reaction was warmed to room temperature and diluted with water. The resultant mixture was extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated to dryness to provide (3-((tert-butyldimethylsilyl)-oxy)-4-cyclobutyl-2-fluorophenyl)boronic acid (1.8 g, 86%). ¹H NMR (500 MHz, CDCl₃), δ 7.39-7.32 (m, 1H), 7.18-7.13 (m, 1H), 5.10-4.97 (m, 2H), 3.82 (t, J=8.8 Hz, 1H), 2.41-2.06 (m, 5H), 2.03-1.95 (m, 1H), 1.03 (s, 9H), 0.19 (s, 6H).

Step D: 3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol

A 50 mL three-neck flask, equipped with a stir bar, nitrogen inlet and temperature probe, was charged with (3-((tert-butyldimethylsilyl)oxy)-4-cyclobutyl-2-fluorophenyl)boronic acid (1.7 g, 5.3 mmol), toluene (4.7 mL), DMF (2.8 mL) and water (4.7 mL). The solvent mixture was sparged for 30 minutes and then treated with 2-amino-5-bromopyrazine (923 mg, 5.3 mmol), potassium carbonate (2.19 g, 15.8 mmol) and dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II).CH₂Cl₂ (137 mg, 0.17 mmol). The reaction mixture was heated at 80° Celsius for 24 hours. The reaction mixture was then cooled to room temperature, diluted with water (8 mL) and the stirred for two hours. The precipitate was collected by filtration and dried in a vacuum oven at 60° Celsius overnight to give 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (1.2 g, 87%). MS (ESI+) Calcd. for C₁₄H₁₄FN₃O, 260.3; m/z found 260.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO), δ 8.24 (m, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.09 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.57 (s, 2H), 3.81-3.72 (m, 1H), 2.34-2.14 (m, 2H), 2.14-1.69 (m, 4H).

Example 1

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

To a 15 mL round-bottomed flask were added a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (51 mg, 0.20 mmol), 4-trifluoromethylbenzyl bromide (52 mg, 0.22 mmol), powdered KOH (42 mg, 0.75 mmol) and DMSO (2.0 mL). The resultant mixture was stirred at room temperature for 22.5 hours before diluting with 100 mL EtOAc and washing with water (×3). The organic layer was isolated, dried, filtered, and concentrated to dryness. The crude product was subjected to FCC to give the title compound as a pale-yellow solid (54 mg, 66%). MS (ESI): mass calcd. for C₂₂H₁₉F₄N₃O, 417.15; m/z found, 418.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.36-8.26 (dd, J=2.5, 1.4, 1H), 8.02-7.99 (d, J=1.5, 1H), 7.82-7.76 (dd, J=8.8, 0.9, 2H), 7.74-7.68 (m, 2H), 7.59-7.51 (m, 1H), 7.26-7.19 (d, J=8.3, 1H), 6.68 (s, 2H), 5.12 (s, 2H), 3.79-3.69 (p, J=8.9, 1H), 2.26-2.16 (m, 2H), 2.14-2.04 (m, 2H), 2.00-1.88 (m, 1H), 1.83-1.73 (m, 1H).

Example 2

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 3-trifluoromethylbenzyl bromide. MS (ESI): mass calcd. for C₂₂H₁₉F₄N₃O, 417.15; m/z found, 418.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.25 (s, 2H), 7.82-7.78 (d, J=2.0, 1H), 7.76-7.70 (d, J=7.5, 1H), 7.69-7.64 (d, J=7.9, 1H), 7.63-7.56 (m, 2H), 7.26-7.20 (m, 1H), 5.17 (s, 2H), 3.83-3.72 (m, 1H), 2.33-2.22 (m, 2H), 2.21-2.10 (m, 2H), 2.07-1.96 (m, 1H), 1.90-1.80 (m, 1H).

Example 3

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 2-trifluoromethylbenzyl bromide. MS (ESI): mass calcd. for C₂₂H₁₉F₄N₃O, 417.15; m/z found, 418.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.29-8.22 (m, 2H), 7.92-7.86 (d, J=7.7, 1H), 7.79-7.74 (m, 1H), 7.73-7.68 (m, 1H), 7.65-7.59 (m, 1H), 7.58-7.53 (m, 1H), 7.29-7.22 (m, 1H), 5.23 (s, 2H), 3.86-3.72 (m, 1H), 2.30-2.20 (m, 2H), 2.20-2.07 (m, 2H), 2.05-1.91 (m, 1H), 1.90-1.78 (m, 1H).

Example 4

3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic Acid

The title compound was prepared using analogous conditions described in Example 1 using 3-(bromomethyl)benzoic acid. MS (ESI): mass calcd. for C₂₂H₂₀FN₃O₃, 393.15; m/z found, 394.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.32-8.24 (m, 1H), 8.21-8.12 (dd, J=12.3, 1.6, 2H), 8.06-7.98 (m, 1H), 7.73-7.66 (m, 1H), 7.59-7.48 (m, 2H), 7.24-7.19 (d, J=8.2, 1H), 5.13 (s, 2H), 3.85-3.75 (m, 1H), 2.28 (m, 2H), 2.20-2.08 (m, 2H), 2.07-1.96 (m, 1H), 1.90-1.80 (m, 1H).

Example 5

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic Acid

The title compound was prepared using analogous conditions described in Example 1 using 4-(bromomethyl)benzoic acid. MS (ESI): mass calcd. for C₂₂H₂₀FN₃O₃, 393.42; m/z found, 394.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.37-8.31 (d, J=1.5, 1H), 8.23 (s, 1H), 8.09-8.04 (d, J=8.2, 2H), 7.66-7.60 (m, 1H), 7.60-7.56 (d, J=8.0, 2H), 7.27-7.21 (d, J=8.4, 1H), 5.14 (s, 2H), 3.87-3.74 (p, J=8.7, 1H), 2.35-2.22 (m, 2H), 2.20-2.09 (m, 2H), 2.09-1.97 (m, 1H), 1.89-1.82 (m, 1H).

Example 6

5-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 1-(bromomethyl)-3-(methylsulfonyl)benzene. MS (ESI): mass calcd. for C₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) 8.34-8.29 (dd, J=2.3, 1.4, 1H), 8.08-8.03 (m, 1H), 8.03-7.99 (d, J=1.5, 1H), 7.96-7.91 (m, 1H), 7.87-7.82 (m, 1H), 7.75-7.69 (m, 1H), 7.58-7.52 (m, 1H), 7.25-7.20 (d, J=8.3, 1H), 6.71 (s, 2H), 5.15 (s, 2H), 3.80-3.69 (m, 1H), 3.24 (s, 3H), 2.28-2.16 (m, 2H), 2.14-2.03 (m, 2H), 2.02-1.89 (m, 1H), 1.86-1.74 (m, 1H).

Example 7

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 1-(bromomethyl)-4-(methylsulfonyl)benzene. MS (ESI): mass calcd. for C₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.36-8.27 (m, 1H), 8.05-7.95 (m, 3H), 7.81-7.72 (m, 2H), 7.61-7.51 (m, 1H), 7.27-7.18 (d, J=8.2, 1H), 5.13 (s, 2H), 3.81-3.71 (m, 1H), 3.24 (s, 3H), 2.27-2.18 (m, 2H), 2.15-2.05 (m, 2H), 2.02-1.92 (m, 1H), 1.85-1.74 (m, 1H).

Example 8

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 1-(bromomethyl)-2-(trifluoromethoxy)benzene. MS (ESI): mass calcd. for C₂₂H₁₉F₄N₃O₂, 433.14; m/z found, 434.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.33-8.27 (dd, J=2.3, 1.4, 1H), 8.05-8.01 (m, 1H), 7.73-7.68 (dd, J=7.6, 1.8, 1H), 7.59-7.51 (m, 2H), 7.51-7.41 (m, 2H), 7.25-7.20 (d, J=8.2, 1H), 5.07 (s, 2H), 3.78-3.58 (m, 1H), 2.23-2.12 (m, 2H), 2.12-2.01 (m, 2H), 1.96-1.86 (m, 1H), 1.82-1.73 (m, 1H).

Example 9

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 1-(bromomethyl)-3-(trifluoromethoxy)benzene. MS (ESI): mass calcd. for C₂₂H₁₉F₄N₃O₂, 433.14; m/z found, 434.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.33-8.28 (m, 1H), 8.06-8.01 (m, 1H), 7.59-7.52 (m, 2H), 7.52-7.45 (m, 2H), 7.40-7.33 (m, 1H), 7.24-7.18 (d, J=8.2, 1H), 5.09 (s, 2H), 3.77-3.64 (p, J=8.9, 1H), 2.24-2.14 (m, 2H), 2.13-2.01 (m, 2H), 1.98-1.86 (m, 1H), 1.83-1.72 (m, 1H).

Example 10

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 1-(bromomethyl)-4-(trifluoromethoxy)benzene. MS (ESI): mass calcd. for C₂₂H₁₉F₄N₃O₂, 433.14; m/z found, 434.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.33-8.28 (m, 1H), 8.06-8.01 (m, 1H), 7.63-7.58 (m, 2H), 7.57-7.52 (m, 1H), 7.45-7.39 (m, 2H), 7.24-7.20 (d, J=8.2, 1H), 5.04 (s, 2H), 3.76-3.65 (m, 1H), 2.24-2.14 (m, 2H), 2.12-2.02 (m, 2H), 1.99-1.88 (m, 1H), 1.82-1.72 (m, 1H).

Example 11

5-(3-{[4-Chloro-2-(methylsulfonyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 1-(bromomethyl)-4-chloro-2-(methylsulfonyl)benzene. MS (ESI): mass calcd. for C₂₂H₂₁ClFN₃O₃S, 461.10; m/z found, 462.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.30-8.26 (m, 1H), 8.03-8.00 (dd, J=2.9, 1.5, 1H), 8.00-7.97 (d, J=1.7, 1H), 7.95-7.91 (m, 2H), 7.61-7.56 (m, 1H), 7.28-7.23 (d, J=8.3, 1H), 5.45 (s, 2H), 3.83-3.73 (m, 1H), 3.36 (s, 3H), 2.28-2.18 (m, 2H), 2.16-2.04 (m, 2H), 2.01-1.89 (m, 1H), 1.84-1.75 (m, 1H).

Example 12

1-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)ethanone

The title compound was prepared using analogous conditions described in Example 1 using 1-(4-(bromomethyl)phenyl)ethanone. MS (ESI): mass calcd. for C₂₃H₂₂FN₃O₂, 391.17; m/z found, 392.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.33-8.29 (m, 1H), 8.05-7.98 (m, 3H), 7.66-7.61 (m, 2H), 7.57-7.52 (m, 1H), 7.24-7.20 (d, J=8.2, 1H), 5.45 (s, 2H), 3.81-3.78 (m, 1H), 2.61 (s, 3H), 2.28-2.16 (m, 2H), 2.14-2.03 (m, 2H), 1.99-1.89 (m, 1H), 1.84-1.75 (m, 1H).

Example 13

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-3-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 3-chloromethylpyridine. MS (ESI): mass calcd. for C₂₀H₁₉FN₄O, 350.15; m/z found, 351.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 9.03-8.97 (d, J=2.1, 1H), 8.88-8.82 (dd, J=5.3, 1.5, 1H), 8.71-8.65 (m, 1H), 8.28-8.23 (m, 1H), 8.22-8.19 (d, J=1.5, 1H), 8.11-8.06 (m, 1H), 7.66-7.60 (m, 1H), 7.29-7.23 (m, 1H), 5.35-5.28 (s, 2H), 3.91-3.80 (m, 1H), 2.39-2.29 (m, 2H), 2.25-2.15 (m, 2H), 2.12-2.00 (m, 1H), 1.92-1.84 (m, 1H).

Example 14

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-4-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 4-chloromethylpyridine. MS (ESI): mass calcd. for C₂₀H₁₉FN₄O, 350.15; m/z found, 351.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 9.03-8.76 (m, 2H), 8.33-8.16 (m, 4H), 7.67-7.60 (m, 1H), 7.30-7.25 (m, 1H), 5.44 (s, 2H), 3.94-3.85 (m, 1H), 2.42-2.32 (m, 2H), 2.29-2.18 (m, 2H), 2.12-2.02 (m, 1H), 1.95-1.85 (m, 1H).

Example 15

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared using analogous conditions described in Example 1 using 4-bromomethylbenzonitrile. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O, 374.15; m/z found, 375.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.32-8.28 (d, J=1.4, 1H), 8.23 (s, 1H), 7.79-7.75 (m, 2H), 7.69-7.64 (m, 2H), 7.64-7.58 (m, 1H), 7.24-7.20 (m, 1H), 5.12 (s, 2H), 3.84-3.73 (m, 1H), 2.32-2.23 (m, 2H), 2.20-2.09 (m, 2H), 2.08-1.96 (m, 1H), 1.89-1.80 (m, 1H).

Example 16

3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared using analogous conditions described in Example 1 using 3-bromomethylbenzonitrile. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O, 374.15; m/z found, 375.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47-8.42 (dd, J=2.3, 1.5, 1H), 8.10-8.06 (d, J=1.5, 1H), 7.80-7.75 (m, 1H), 7.73-7.67 (m, 1H), 7.65-7.60 (m, 1H), 7.59-7.53 (dd, J=8.2, 7.4, 1H), 7.52-7.47 (m, 1H), 7.18-7.13 (m, 1H), 5.05 (s, 2H), 4.64 (s, 2H), 3.81-3.67 (m, 1H), 2.34-2.22 (m, 2H), 2.19-2.06 (m, 2H), 2.06-1.94 (m, 1H), 1.92-1.78 (m, 1H).

Example 17

3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide

The title compound was obtained as a side product in the formation of 3-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile, Example 16. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂, 392.16; m/z found, 393.2 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.28-8.22 (dd, J=5.9, 1.5, 2H), 8.03-7.98 (m, 1H), 7.90-7.83 (m, 1H), 7.69-7.64 (m, 1H), 7.61-7.55 (m, 1H), 7.53-7.47 (m, 1H), 7.24-7.19 (dd, J=7.4, 1.0, 1H), 5.13 (s, 2H), 3.86-3.75 (m, 1H), 2.33-2.21 (m, 2H), 2.19-2.08 (m, 2H), 2.08-1.96 (m, 1H), 1.91-1.79 (m, 1H).

Example 18

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared using analogous conditions described in Example 1 using 2-bromomethylbenzonitrile. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O, 374.15; m/z found, 375.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.35-8.28 (dd, J=2.5, 1.4, 1H), 8.03-7.97 (d, J=1.5, 1H), 7.95-7.89 (m, 1H), 7.83-7.72 (m, 2H), 7.64-7.52 (m, 2H), 7.25-7.18 (d, J=8.3, 1H), 6.68 (s, 2H), 5.20 (s, 2H), 3.77-3.65 (m, 1H), 2.25-2.12 (m, 2H), 2.12-2.01 (m, 2H), 1.96-1.85 (m, 1H), 1.83-1.70 (m, 1H).

Example 19

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide

The title compound was obtained as a side product in the formation of 2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile, Example 18. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂, 392.16; m/z found, 393.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.27 (s, 1H), 8.22-8.16 (d, J=1.5, 1H), 7.77-7.72 (dd, J=7.8, 1.2, 1H), 7.63-7.59 (dd, J=7.6, 1.3, 1H), 7.59-7.52 (m, 2H), 7.46-7.41 (m, 1H), 7.26-7.21 (d, J=8.2, 1H), 5.30 (s, 2H), 3.89-3.77 (p, J=8.8, 1H), 2.35-2.23 (m, 2H), 2.20-2.09 (m, 2H), 2.07-1.96 (m, 1H), 1.89-1.78 (m, 1H).

Example 20

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

To a 20 mL vial were added a stir bar, 4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile (82 mg, 0.22 mmol), NaN₃ (576 mg, 8.85 mmol), NH₄Cl (557 mg, 10.4 mmol) and dry DMF (2.0 mL). The resultant mixture was heated at 125° Celsius for 21.5 hours before cooling to rt. The mixture was then passed through a syringe filter and the filtrate subjected to HPLC purification to give the title compound as a yellow solid (47 mg, 40%). MS (ESI): mass calcd. for C₂₂H₂₀FN₇O, 417.17; m/z found, 418.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.35-8.29 (m, 1H), 8.12-8.06 (m, 2H), 8.04-7.97 (d, J=1.5, 1H), 7.77-7.69 (d, J=7.9, 2H), 7.60-7.51 (m, 1H), 7.24-7.19 (d, J=8.3, 1H), 5.13 (s, 2H), 3.84-3.71 (m, 1H), 2.28-2.18 (m, 2H), 2.17-2.03 (m, 2H), 2.02-1.90 (m, 1H), 1.84-1.74 (m, 1H).

Example 21

5-(4-Cyclobutyl-2-fluoro-3-{[3-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 20 starting from 3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile. MS (ESI): mass calcd. for C₂₂H₂₀FN₇O, 417.17; m/z found, 418.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.35-8.30 (m, 1H), 8.24-8.19 (m, 1H), 8.08-8.01 (m, 2H), 7.73-7.63 (m, 2H), 7.60-7.52 (m, 1H), 7.26-7.19 (d, J=8.2, 1H), 5.13 (s, 2H), 3.83-3.72 (m, 1H), 2.29-2.18 (m, 2H), 2.15-2.04 (m, 2H), 2.00-1.87 (m, 1H), 1.84-1.73 (m, 1H).

Example 22

5-(4-Cyclobutyl-2-fluoro-3-{[2-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 20 starting from 2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-benzonitrile. MS (ESI): mass calcd. for C₂₂H₂₀FN₇O, 417.17; m/z found, 418.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.28-8.23 (m, 1H), 8.01-7.97 (d, J=1.5, 1H), 7.90-7.85 (d, J=7.7, 1H), 7.82 (s, 1H), 7.73-7.66 (m, 1H), 7.64-7.57 (d, J=7.7, 1H), 7.55-7.49 (m, 1H), 7.21-7.14 (d, J=8.3, 1H), 6.66 (s, 2H), 5.37 (s, 2H), 3.57-3.46 (m, 1H), 2.15-2.04 (m, 2H), 2.04-1.94 (m, 2H), 1.93-1.82 (m, 1H), 1.79-1.68 (m, 1H).

Example 23

(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)acetic Acid

The title compound was prepared using analogous conditions described in Example 1 using 2-(4-(bromomethyl)phenyl)acetic acid. MS (ESI): mass calcd. for C₂₃H₂₂FN₃O₃, 407.16; m/z found, 408.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.31-8.15 (m, 2H), 7.60 (s, 1H), 7.54-7.47 (m, 1H), 7.44-7.37 (d, J=7.9, 2H), 7.33-7.29 (d, J=7.8, 2H), 7.19-7.14 (d, J=8.2, 1H), 5.01 (s, 2H), 3.81-3.68 (m, 1H), 3.61 (s, 2H), 2.32-2.20 (m, 2H), 2.18-2.05 (m, 2H), 2.04-1.94 (m, 1H), 1.88-1.77 (m, 1H).

Example 24

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-2-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 1 using 2-chloromethylpyridine. MS (ESI): mass calcd. for C₂₀H₁₉FN₄O, 350.15; m/z found, 351.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.57-8.52 (m, 1H), 8.32-8.28 (dd, J=2.3, 1.5, 1H), 8.06-8.02 (d, J=1.5, 1H), 7.95-7.90 (m, 1H), 7.74-7.69 (m, 1H), 7.55-7.50 (m, 1H), 7.44-7.37 (m, 1H), 7.24-7.18 (m, 1H), 5.16 (s, 2H), 3.86-3.75 (m, 1H), 2.32-2.22 (m, 2H), 2.20-2.08 (m, 2H), 2.07-1.94 (m, 1H), 1.89-1.79 (m, 1H).

Example 25

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N,N-dimethylbenzenesulfonamide

The title compound was prepared using analogous conditions described in Example 1 using 4-(bromomethyl)-N,N-dimethylbenzenesulfonamide. MS (ESI): mass calcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.50-8.44 (d, J=1.4, 1H), 8.19-8.11 (m, 1H), 7.83-7.74 (m, 2H), 7.69-7.58 (m, 3H), 7.19-7.13 (d, J=8.3, 1H), 5.06 (s, 2H), 3.82-3.67 (m, 1H), 2.74 (s, 6H), 2.35-2.19 (m, 2H), 2.19-2.05 (m, 2H), 2.05-1.92 (m, 2H), 1.89-1.77 (m, 1H).

Example 26

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzenesulfonamide

The title compound was prepared using analogous conditions described in Example 1 using 4-(bromomethyl)benzenesulfonamide. MS (ESI): mass calcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.33-8.30 (dd, J=2.4, 1.4, 1H), 8.02-7.99 (d, J=1.5, 1H), 7.90-7.84 (m, 2H), 7.70-7.64 (m, 2H), 7.58-7.52 (m, 1H), 7.39 (s, 2H), 7.25-7.19 (d, J=8.3, 1H), 5.11 (s, 2H), 3.79-3.63 (m, 1H), 2.28-2.16 (m, 2H), 2.16-2.03 (m, 2H), 2.02-1.88 (m, 1H), 1.84-1.74 (m, 1H).

Example 27

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N-methylbenzenesulfonamide

The title compound was prepared using analogous conditions described in Example 1 using 4-(bromomethyl)-N-methylbenzenesulfonamide. MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.34-8.29 (dd, J=2.3, 1.4, 1H), 8.05-7.99 (d, J=1.4, 1H), 7.86-7.79 (m, 2H), 7.73-7.67 (m, 2H), 7.60-7.53 (m, 1H), 7.51-7.44 (m, 1H), 7.25-7.19 (d, J=8.2, 1H), 5.12 (s, 2H), 3.79-3.67 (m, 1H), 2.46-2.37 (d, J=5.0, 3H), 2.27-2.15 (m, 2H), 2.15-2.02 (m, 2H), 2.02-1.88 (m, 1H), 1.84-1.72 (m, 1H).

Example 28

5-{4-Cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

To a solution of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol) and 1-(bromomethyl)-4-fluorobenzene (36 μL, 0.29 mmol) in DMSO (1 mL) was added 1 pellet (˜125 mg) of potassium hydroxide. The reaction was stirred for 16 hours at room temperature before filtering and purifying by HPLC to give 5-{4-cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine (37 mg, 39%). MS (ESI): mass calcd. for C₂₁H₁₉F₂N₃O, 367.15; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) 8.30 (d, J=1.3, 1H), 8.22 (s, 1H), 7.58 (m, 1H), 7.50-7.43 (m, 2H), 7.20 (d, J=8.0, 1H), 7.15-7.07 (m, 2H), 5.01 (s, 2H), 3.83-3.68 (m, 1H), 2.31-2.21 (m, 2H), 2.18-1.93 (m, 3H), 1.87-1.78 (m, 1H).

Example 29

5-{4-Cyclobutyl-2-fluoro-3-[(3-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-3-fluorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉F₂N₃O, 367.15; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J=4.5, 2H), 7.58 (m, 1H), 7.43-7.37 (m, 1H), 7.29-7.19 (m, 3H), 7.11-7.04 (m, 1H), 5.05 (d, J=9.9, 2H), 3.86-3.73 (m, 1H), 2.34-2.21 (m, 2H), 2.20-1.95 (m, 3H), 1.91-1.80 (m, 1H).

Example 30

5-{4-Cyclobutyl-2-fluoro-3-[(2-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2-fluorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉F₂N₃O, 367.15; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.32 (d, J=1.2, 1H), 8.22 (s, 1H), 7.59 (m, 1H), 7.53-7.48 (m, 1H), 7.42-7.35 (m, 1H), 7.24-7.09 (m, 3H), 5.11 (s, 2H), 3.81-3.67 (m, 1H), 2.29-2.17 (m, 2H), 2.15-1.91 (m, 3H), 1.88-1.75 (m, 1H).

Example 31

5-{4-Cyclobutyl-3-[(2,6-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-1,3-difluorobenzene. MS (ESI): mass calcd. for C₂₁H₁₈F₃N₃O, 385.14; m/z found, 386.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1H), 8.18 (d, J=1.4, 1H), 7.59-7.52 (m, 1H), 7.48-7.39 (m, 1H), 7.20 (d, J=7.6, 1H), 7.05-6.97 (m, 2H), 5.19 (s, 2H), 3.80-3.66 (m, 1H), 2.26-2.15 (m, 2H), 2.13-1.91 (m, 3H), 1.86-1.79 (m, 1H).

Example 32

5-{4-Cyclobutyl-3-[(2,3-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2,3-difluorobenzene. MS (ESI): mass calcd. for C₂₁H₁₈F₃N₃O, 385.14; m/z found, 386.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J=1.2, 1H), 8.23 (s, 1H), 7.59 (m, 1H), 7.36-7.13 (m, 4H), 5.15 (d, J=1.0, 2H), 3.82-3.69 (m, 1H), 2.29-2.19 (m, 2H), 2.17-1.92 (m, 3H), 1.90-1.78 (m, 1H).

Example 33

5-{4-Cyclobutyl-3-[(3,4-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-(bromomethyl)-1,2-difluorobenzene. MS (ESI): mass calcd. for C₂₁H₁₈F₃N₃O, 385.14; m/z found, 386.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J=1.3, 1H), 8.23 (s, 1H), 7.59 (m, 1H), 7.45-7.36 (m, 1H), 7.33-7.20 (m, 3H), 5.02 (s, 2H), 3.85-3.72 (m, 1H), 2.34-2.23 (m, 2H), 2.21-1.97 (m, 3H), 1.90-1.81 (m, 1H).

Example 34

5-{3-[(2-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2-chlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉ClFN₃O, 383.12; m/z found, 384.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.23 (m, 2H), 7.63-7.56 (m, 2H), 7.47-7.42 (m, 1H), 7.38-7.32 (m, 2H), 7.22 (d, J=7.8, 1H), 5.16 (d, J=3.7, 2H), 3.85-3.72 (m, 1H), 2.29-2.20 (m, 2H), 2.18-1.91 (m, 3H), 1.88-1.78 (m, 1H).

Example 35

5-{3-[(3-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-3-chlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉ClFN₃O, 383.12; m/z found, 384.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 2H), 7.60-7.54 (m, 1H), 7.49 (s, 1H), 7.39-7.33 (m, 3H), 7.21 (d, J=8.3, 1H), 5.04 (s, 2H), 3.84-3.70 (m, 1H), 2.32-2.21 (m, 2H), 2.20-1.94 (m, 3H), 1.91-1.79 (m, 1H).

Example 36

5-{3-[(4-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-4-chlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉ClFN₃O, 383.12; m/z found, 384.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.31 (d, J=1.3, 1H), 8.22 (s, 1H), 7.62-7.55 (m, 1H), 7.46-7.36 (m, 4H), 7.20 (d, J=7.9, 1H), 5.00 (d, J=9.7, 2H), 3.82-3.69 (m, 1H), 2.31-2.20 (m, 2H), 2.17-1.93 (m, 3H), 1.90-1.78 (m, 1H).

Example 37

5-{4-Cyclobutyl-3-[(2,6-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-1,3-dichlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₈Cl₂FN₃O, 417.08; m/z found, 418.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J=1.4, 1H), 8.21 (t, J=1.4, 1H), 7.62-7.56 (m, 1H), 7.47-7.41 (m, 2H), 7.38-7.31 (m, 1H), 7.22 (d, J=7.7, 1H), 5.42 (s, 2H), 3.84-3.70 (m, 1H), 2.19-1.75 (m, 6H).

Example 38

5-{4-Cyclobutyl-3-[(2,5-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-1,4-dichlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₈Cl₂FN₃O, 417.08; m/z found, 418.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.21 (m, 2H), 7.66 (d, J=2.5, 1H), 7.59 (m, 1H), 7.47-7.41 (m, 1H), 7.39-7.34 (m, 1H), 7.24 (m, 1H), 5.13 (s, 2H), 3.86-3.73 (m, 1H), 2.33-2.22 (m, 2H), 2.20-2.09 (m, 2H), 2.07-1.96 (m, 1H), 1.92-1.79 (m, 1H).

Example 39

5-{4-Cyclobutyl-3-[(2,3-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2,3-dichlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₈Cl₂FN₃O, 417.08; m/z found, 418.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 2H), 7.62-7.52 (m, 3H), 7.35 (m, 1H), 7.23 (d, J=8.3, 1H), 5.19 (s, 2H), 3.86-3.73 (m, 1H), 2.29-1.78 (m, 7H).

Example 40

5-{4-Cyclobutyl-3-[2,4-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2,4-dichlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₈Cl₂FN₃O, 417.08; m/z found, 418.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J=1.3, 1H), 8.24 (s, 1H), 7.63-7.57 (m, 2H), 7.53 (d, J=2.1, 1H), 7.41-7.37 (m, 1H), 7.23 (d, J=7.9, 1H), 5.14 (s, 2H), 3.84-3.72 (m, 1H), 2.30-2.20 (m, 2H), 2.18-1.95 (m, 3H), 1.89-1.79 (m, 1H).

Example 41

5-{4-Cyclobutyl-3-[(3,4-dimethylbenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-(bromomethyl)-1,2-dimethylbenzene. MS (ESI): mass calcd. for C₂₃H₂₄FN₃O, 377.19; m/z found, 378.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.29-8.21 (m, 2H), 7.60-7.53 (m, 1H), 7.23-7.02 (m, 4H), 5.02 (d, J=43.3, 2H), 3.82-3.67 (m, 1H), 2.38 (s, 1H), 2.33 (s, 1H), 2.29-2.16 (m, 6H), 2.15-1.92 (m, 3H), 1.89-1.78 (m, 1H).

Example 42

5-(3-{[2-Chloro-3-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene. MS (ESI): mass calcd. for C₂₂H₁₈ClF₄N₃O, 451.11; m/z found, 452.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.30-8.22 (m, 2H), 7.91 (d, J=7.7, 1H), 7.83-7.77 (m, 1H), 7.64-7.52 (m, 2H), 7.24 (d, J=7.9, 1H), 5.23 (d, J=6.5, 2H), 3.84-3.72 (m, 1H), 2.30-2.18 (m, 2H), 2.17-2.07 (m, 2H), 2.07-1.93 (m, 1H), 1.88-1.79 (m, 1H).

Example 43

5-(3-{[5-Chloro-2-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-4-chloro-1-(trifluoromethyl)benzene. MS (ESI): mass calcd. for C₂₂H₁₈ClF₄N₃O, 451.11; m/z found, 452.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 2H), 7.92 (s, 1H), 7.75 (d, J=8.5, 1H), 7.66-7.60 (m, 1H), 7.57 (d, J=8.4, 1H), 7.27 (d, J=7.9, 1H), 5.21 (s, 2H), 3.85-3.73 (m, 1H), 2.33-2.23 (m, 2H), 2.20-2.11 (m, 2H), 2.07-1.96 (m, 1H), 1.91-1.82 (m, 1H).

Example 44

5-(4-Cyclobutyl-2-fluoro-3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene. MS (ESI): mass calcd. for C₂₂H₁₈F₅N₃O, 435.14; m/z found, 436.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J=1.3, 1H), 8.23 (s, 1H), 7.92-7.86 (m, 1H), 7.61 (m, 1H), 7.55-7.51 (m, 1H), 7.49-7.43 (m, 1H), 7.24 (d, J=8.0, 1H), 5.18 (s, 2H), 3.83-3.70 (m, 1H), 2.29-2.19 (m, 2H), 2.18-2.08 (m, 2H), 2.06-1.93 (m, 1H), 1.90-1.79 (m, 1H).

Example 45

5-{3-[(2-Chloro-5-fluorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-1-chloro-4-fluorobenzene. MS (ESI): mass calcd. for C₂₁H₁₈ClF₂N₃O, 401.11; m/z found, 402.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (m, 2H), 7.64-7.57 (m, 1H), 7.48-7.40 (m, 2H), 7.23 (d, J=7.9, 1H), 7.16-7.08 (m, 1H), 5.13 (s, 2H), 3.87-3.75 (m, 1H), 2.33-2.21 (m, 2H), 2.21-1.94 (m, 3H), 1.90-1.80 (m, 1H).

Example 46

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic Acid

The title compound was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and ethyl 2-(bromomethyl)benzoate. MS (ESI): mass calcd. for C₂₂H₂₀FN₃O₃, 393.15; m/z found, 394.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.30 (d, J=1.0, 1H), 8.22 (s, 1H), 8.06-8.02 (m, 1H), 7.87 (d, J=7.7, 1H), 7.66-7.56 (m, 2H), 7.44 (m, 1H), 7.22 (d, J=8.3, 1H), 5.47 (s, 2H), 3.87-3.72 (m, 1H), 2.31-2.20 (m, 2H), 2.17-2.07 (m, 2H), 2.05-1.92 (m, 1H), 1.87-1.77 (m, 1H).

Example 47

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 3-(bromomethyl)-1-methyl-1H-pyrazole. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.16; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.30-8.25 (m, 1H), 8.18 (m, 1H), 7.58-7.51 (m, 2H), 7.19 (d, J=8.3, 1H), 6.34 (m, 1H), 5.03 (d, J=5.7, 2H), 3.88 (d, J=6.0, 3H), 3.82-3.71 (m, 1H), 2.30-2.20 (m, 2H), 2.15-1.95 (m, 3H), 1.89-1.79 (m, 1H).

Example 48

5-{4-Cyclobutyl-3-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methoxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 5-(bromomethyl)-3-cyclopropyl-1,2,4-oxadiazole. MS (ESI): mass calcd. for C₂₀H₂₀FN₅O₂, 381.16; m/z found, 382.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J=1.6, 1H), 8.16 (d, J=1.4, 1H), 7.59 (m, 1H), 7.22 (d, J=8.3, 1H), 5.26 (d, J=6.7, 2H), 3.85-3.74 (m, 1H), 2.36-2.25 (m, 2H), 2.20-2.01 (m, 4H), 1.92-1.82 (m, 1H), 1.14-1.05 (m, 2H), 1.01-0.95 (m, 2H).

Example 49

tert-Butyl [3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetate

To a 4 mL vial were added a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (47 mg, 0.18 mmol), tert-butyl bromoacetate (35 μL, 0.24 mmol), powdered KOH (19 mg, 0.34 mmol) and DMSO (1.0 mL). The resultant mixture was stirred at room temperature for 19 hours before passing it through a syringe filter and subjecting the filtrate to HPLC purification to give both the title compound (20 mg, 22%) and recovered 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (20 mg, 26%). MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₃, 373.18; m/z found, 374.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.44-8.38 (d, J=1.4, 1H), 8.21-8.16 (d, J=1.4, 1H), 7.64-7.57 (m, 1H), 7.17-7.10 (m, 1H), 4.57-4.49 (d, J=1.3, 2H), 3.99-3.88 (m, 1H), 2.41-2.30 (m, 2H), 2.18-1.99 (m, 3H), 1.91-1.79 (m, 1H), 1.50 (s, 9H).

Example 50

[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetic acid

To a 20 mL vial containing tert-butyl [3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetate (17 mg, 0.034 mmol) were added a stir bar and formic acid (1 mL). The reaction mixture was stirred for 20 hours at room temperature and then concentrated to dryness to give the title compound (12 mg, 95%). MS (ESI): mass calcd. for C₁₆H₁₆FN₃O₃, 317.12; m/z found, 318.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.25 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.55-7.49 (m, 1H), 7.22-7.16 (d, J=8.2, 1H), 4.65 (s, 2H), 4.04-3.86 (p, J=8.7, 1H), 2.42-2.31 (m, 2H), 2.25-2.12 (m, 2H), 2.12-2.00 (m, 1H), 1.94-1.80 (m, 1H).

Example 51

Racemic 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridin-2(1H)-one

To a 5 mL reaction tube equipped with reflux condenser and under nitrogen, were added 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (100 mg, 0.317 mmol), Cs₂CO₃ (103 mg, 0.317 mmol), pyridin-2(1H)-one (151 mg, 1.59 mmol) and DMF (2 mL) to give a yellow suspension. The resulting mixture was heated at 80° Celsius for 3 hours. The mixture was then concentrated to dryness, and the residue purified by HPLC to afford the title compound (110 mg, 85%). MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₃, 410.18; m/z found, 411.1 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (dd, J=2.4, 1.5, 1H), 8.00 (m, 1H), 7.66-7.60 (m, 1H), 7.52 (m, 1H), 7.46-7.39 (m, 1H), 7.21 (d, J=8.2, 1H), 6.65 (s, 2H), 6.40 (dd, J=9.1, 0.8, 1H), 6.21 (m, 1H), 5.40 (d, J=5.8, 1H), 4.35 (dd, J=13.0, 3.8, 1H), 4.18-4.08 (m, 1H), 3.93 (d, J=5.1, 2H), 3.85 (dd, J=17.8, 8.9, 1H), 3.74 (dd, J=13.0, 8.4, 1H), 2.30 (m, 2H), 2.13-2.04 (m, 2H), 2.03-1.94 (m, 1H), 1.88-1.78 (m, 1H).

Example 52

Racemic 3-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrimidin-4(3H)-one

The title compound was prepared using analogous conditions described in Example 51 using pyrimidin-4(3H)-one. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O₃, 411.17; m/z found, 412.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.31-8.27 (m, 1H), 8.00 (d, J=1.5, 1H), 7.92 (d, J=6.6, 1H), 7.52 (m, 1H), 7.22 (d, J=8.2, 1H), 6.65 (s, 2H), 6.43 (dd, J=6.6, 0.7, 1H), 5.53 (s, 1H), 4.37 (dd, J=13.2, 3.3, 1H), 4.11 (dd, J=8.7, 3.5, 1H), 3.96 (d, J=5.3, 2H), 3.90-3.82 (m, 1H), 3.80-3.74 (m, 1H), 2.32 (m, 2H), 2.10 (m, 2H), 2.04-1.92 (m, 1H), 1.86-1.77 (m, 1H).

Example 53

Racemic 2-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridazin-3(2H)-one

The title compound was prepared using analogous conditions described in Example 51 using pyridazin-3(2H)-one. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O₃, 411.17; m/z found, 412.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.30-8.25 (m, 1H), 7.99 (d, J=1.5, 1H), 7.93 (dd, J=3.8, 1.7, 1H), 7.50 (m, 1H), 7.41 (dd, J=9.4, 3.8, 1H), 7.20 (d, J=8.2, 1H), 6.95 (dd, J=9.4, 1.6, 1H), 6.64 (s, 2H), 5.31 (d, J=5.7, 1H), 4.30 (m, 1H), 4.22 (d, J=6.6, 2H), 3.98-3.91 (m, 2H), 3.90-3.79 (m, 1H), 2.28 (dd, J=14.3, 7.8, 2H), 2.08 (dd, J=19.5, 9.4, 2H), 2.03-1.95 (m, 1H), 1.86-1.75 (m, 1H).

Example 54

Racemic 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrazin-2(1H)-one

The title compound was prepared using analogous conditions described in Example 51 using pyrazin-2(1H)-one. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O₃, 411.17; m/z found, 412.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=1.5, 1H), 8.07 (dd, J=9.7, 1.3, 2H), 7.66 (dd, J=4.3, 1.1, 1H), 7.58 (m, 1H), 7.39 (d, J=4.3, 1H), 7.28 (d, J=8.2, 1H), 6.70 (s, 2H), 5.54 (s, 1H), 4.41 (dd, J=12.9, 3.4, 1H), 4.22 (s, 1H), 4.02 (d, J=5.2, 2H), 3.91 (dd, J=17.8, 8.8, 1H), 3.82 (dd, J=12.9, 9.0, 1H), 2.41-2.33 (m, 2H), 2.15 (dd, J=19.1, 9.5, 2H), 2.06 (dd, J=18.7, 9.0, 1H), 1.94-1.83 (m, 1H).

Example 55

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-5-ylamino)propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 using 5-aminopyrimidine. MS (ESI): mass calcd. for C₂₁H₂₃FN₆O₂, 410.19; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.26-8.21 (m, 1H), 8.17 (s, 2H), 7.95 (d, J=1.4, 1H), 7.47 (m, 1H), 7.17 (d, J=8.2, 1H), 6.60 (s, 2H), 6.11 (t, J=6.0, 1H), 5.26 (s, 1H), 4.03-3.91 (m, 3H), 3.85-3.74 (m, 1H), 3.24-3.11 (m, 2H), 2.28-2.16 (m, 2H), 2.10-1.98 (m, 2H), 1.93-1.81 (m, 1H), 1.80-1.69 (m, 1H).

Example 56

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-2-ylamino)propan-2-ol Step A: 1-Amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol

A mixture of 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (500 mg, 1.59 mmol) and 6 N NH₃ in MeOH (5 mL) was stirred in a sealed tube at 60° Celsius for approximately 8 hours before cooling to rt and concentrating to dryness to give 1-amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol (510 mg, 96%).

Step B

To a 25 mL round-bottomed flask were added a stir bar, 1-amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol (150 mg, 0.45 mmol), 2-chloropyrimidine (62 mg, 0.54 mmol), Cs₂CO₃ (440 mg, 1.35 mmol) and DMF (6 mL). The mixture was stirred at 60 Celsius for approximately 24 hours and then diluted with water (20 mL). The aqueous mixture was extracted with EtOAc (3×30 mL) and the combined extracts dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by HPLC to afford the title compound (25 mg, 55%). MS (ESI): mass calcd. for C₂₁H₂₃FN₆O₂, 410.19; m/z found, 411.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.33-8.18 (m, 3H), 7.95 (d, J=1.4, 1H), 7.45 (m, 1H), 7.15 (d, J=8.2, 1H), 6.98 (m, 1H), 6.61 (s, 2H), 6.54 (m, 1H), 5.19 (d, J=5.3, 1H), 4.03-3.96 (m, 1H), 3.94-3.85 (m, 2H), 3.83-3.75 (m, 1H), 3.49-3.42 (m, 2H), 2.26-2.17 (m, 2H), 2.09-1.97 (m, 2H), 1.93-1.84 (m, 1H), 1.80-1.71 (m, 1H).

Example 57

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrazin-2-ylamino)propan-2-ol

The title compound was prepared using analogous conditions described in Example 56 using 2-chloropyrazine. MS (ESI): mass calcd. for C₂₁H₂₃FN₆O₂, 410.19; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.22-6.96 (m, 2H), 6.60 (s, 2H), 5.23 (s, 1H), 3.98 (s, 2H), 3.91 (s, 2H), 3.79 (s, 2H), 2.21 (s, 2H), 2.03 (s, 2H), 1.86 (d, J=8.5, 1H), 1.76 (s, 1H).

Example 58

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((5-aminopyrimidin-2-yl)amino)propan-2-ol

The title compound was prepared using analogous conditions described in Example 56 using 2-chloro-5-aminopyrimidine. ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.31-8.25 (m, 1H), 8.00 (d, J=1.5, 1H), 7.94 (s, 2H), 7.49 (m, 1H), 7.19 (d, J=8.3, 1H), 6.64 (s, 2H), 6.38 (m, 1H), 5.18 (d, J=5.2, 1H), 4.04-3.80 (m, 4H), 3.44 (m, 2H), 2.32-2.21 (m, 2H), 2.06 (m, 2H), 1.92 (m, 1H), 1.80 (m, 1H).

Example 59

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((6-aminopyrimidin-4-yl)amino)propan-2-ol

The title compound was prepared using analogous conditions described in Example 56 using 4-amino-6-chloropyrimidine. MS (ESI): mass calcd. for C₂₁H₂₄FN₇O₂, 425.20; m/z found, 426.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.47 (m, 1H), 7.18 (d, J=8.3, 1H), 6.61 (s, 2H), 6.54 (s, 1H), 6.02 (s, 2H), 5.43 (s, 1H), 5.34 (s, 1H), 3.98-3.78 (m, 6H), 2.24 (s, 2H), 2.10-2.01 (m, 2H), 1.92 (dd, J=18.5, 9.0, 1H), 1.77 (d, J=9.1, 1H).

Example 60

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-pyrazol-1-yl)propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 using pyrazole. MS (ESI): mass calcd. for C₂₀H₂₂FN₅O₂, 383.18; m/z found, 384.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1H), 8.01 (s, 1H), 7.54-7.42 (m, 3H), 7.08 (d, J=8.2, 1H), 6.23 (d, J=1.9, 1H), 4.64 (s, 2H), 4.43 (dd, J=16.1, 5.7, 1H), 4.32 (m, 2H), 3.89 (dd, J=9.6, 4.8, 1H), 3.83 (dd, J=9.6, 5.5, 1H), 3.73 (dd, J=17.6, 8.5, 1H), 2.31-2.22 (m, 2H), 2.07 (dd, J=18.7, 9.2, 2H), 2.02-1.93 (m, 1H), 1.84-1.77 (m, 1H).

Example 61

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-imidazol-1-yl)propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 using imidazole. MS (ESI): mass calcd. for C₂₀H₂₂FN₅O₂, 383.18; m/z found, 384.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.32 (s, 1H), 7.99 (s, 1H), 7.48 (m, 1H), 7.09 (d, J=8.3, 1H), 6.11 (s, 2H), 4.83 (s, 1H), 4.32-4.08 (m, 3H), 3.92 (d, J=12.2, 2H), 3.71 (m, 1H), 2.31-2.21 (m, 2H), 2.14-2.03 (m, 2H), 2.02-1.93 (m, 1H), 1.81 (dd, J=19.5, 8.6, 1H).

Example 62

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 using 1,2,4-triazole. MS (ESI): mass calcd. for C₁₉H₂₁FN₆O₂, 384.17; m/z found, 385.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.36 (s, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.50 (m, 1H), 7.09 (d, J=8.3, 1H), 4.63 (s, 2H), 4.48 (dd, J=16.7, 6.1, 1H), 4.35 (dd, J=14.0, 4.7, 2H), 3.93 (d, J=4.2, 2H), 3.70 (dd, J=17.6, 8.7, 1H), 2.28 (m, 2H), 2.09 (dd, J=14.4, 5.4, 2H), 2.03-1.95 (m, 1H), 1.82 (dd, J=19.2, 8.7, 1 H).

Example 63

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,3-triazol-1-yl)propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 using 1,2,3-triazole. MS (ESI): mass calcd. for C₁₉H₂₁FN₆O₂, 384.17; m/z found, 385.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.38-8.32 (m, 1H), 8.01 (d, J=1.5, 1H), 7.71 (d, J=0.8, 1H), 7.68 (d, J=3.8, 1H), 7.51 (m, 1H), 7.09 (d, J=8.2, 1H), 4.75-4.60 (m, 3H), 4.53 (dd, J=14.1, 7.1, 1H), 4.39 (dd, J=13.1, 8.0, 1H), 3.98 (dd, J=9.8, 4.9, 1H), 3.89 (dd, J=9.9, 5.9, 1H), 3.71 (m, 1H), 3.38-3.13 (m, 1H), 2.27 (m, 2H), 2.14-2.05 (m, 2H), 2.03-1.94 (m, 1H), 1.81 (m, 1H).

Example 64

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(2H-1,2,3-triazol-2-yl)propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 using 1,2,3-triazole. MS (ESI): mass calcd. for C₁₉H₂₁FN₆O₂, 384.17; m/z found, 385.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 8.39-8.35 (m, 1H), 8.01 (d, J=1.5, 1H), 7.60 (d, J=1.7, 2H), 7.52-7.46 (m, 1H), 7.08 (d, J=8.3, 1H), 4.76 (dd, J=13.9, 4.0, 1H), 4.67 (d, J=7.2, 1H), 4.64 (d, J=7.2, 2H), 4.49-4.42 (m, 1H), 4.03-3.92 (m, 2H), 3.75 (m, 1H), 3.53-3.35 (m, 1H), 2.32-2.22 (m, 2H), 2.12-2.04 (m, 2H), 1.98 (m, 1H), 1.85-1.75 (m, 1H).

Example 65

Racemic 5-Amino-1-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile

The title compound was prepared using analogous conditions described in Example 51 using 3-amino-4-cyanopyrazole. MS (ESI): mass calcd. for C₂₁H₂₂FN₇O₂, 423.18; m/z found, 424.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H), 7.95 (s, 1H), 7.59-7.34 (m, 2H), 7.17 (d, J=8.0, 1H), 6.61 (s, 2H), 6.44 (s, 2H), 5.44 (s, 1H), 4.22-4.11 (m, 1H), 4.07-3.96 (m, 2H), 3.92-3.86 (m, 2H), 3.84-3.76 (m, 1H), 2.29-2.20 (m, 2H), 2.08-1.93 (m, 3H), 1.82-1.73 (m, 1H).

Example 66

Racemic 1-(5-Amino-1H-1,2,3-triazol-1-yl)-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol Step A: 1H-1,2,3-Triazol-5-amine

To a 25 mL round-bottomed flask were added a stir bar, 5-nitro-1H-1,2,3-triazole (300 mg, 2.63 mmol), Raney-Ni (30 mg), and MeOH (5 mL). The flask was subjected to 1 atm of H₂ and stirred at room temperature for approximately 3 hours. The mixture was then filtered, and the filtrate was concentrated to dryness to give 1H-1,2,3-triazol-5-amine (181 mg, yield: 82%).

Step B

The title compound was prepared using analogous conditions described in Example 51 using 1H-1,2,3-triazol-5-amine. MS (ESI): mass calcd. for C₁₉H₂₂FN₇O₂, 399.18; m/z found, 400.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 7.98 (s, 1H), 7.53-7.42 (m, 1H), 7.18 (d, J=8.5, 1H), 6.86 (s, 1H), 6.63 (s, 2H), 5.35 (d, J=4.8, 1H), 4.95 (s, 2H), 4.33-4.16 (m, 3H), 3.89 (s, 2H), 3.85-3.79 (m, 1H), 2.32-2.21 (m, 2H), 2.12-1.92 (m, 3H), 1.82-1.73 (m, 1H).

Example 67

Racemic 1-((1H-Pyrazol-5-yl)amino)-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol

A mixture of 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (200 mg, 0.63 mmol), 3-aminopyrazole (79 mg, 0.95 mmol), Yb(OTf)₃ (80 mg, 0.13 mmol) and DMF (1 mL) was stirred at 100 Celsius for approximately 24 hours. The mixture was concentrated to dryness and the residue purified by HPLC to give the title compound (15%, 37 mg). MS (ESI): mass calcd. for C₂₀H₂₃FN₆O₂, 398.19; m/z found, 399.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d); 8.25 (s, 1H), 7.97 (d, J=1.4, 1H), 7.50-7.42 (m, 1H), 7.30 (d, J=1.9, 1H), 7.17 (d, J=8.3, 1H), 6.63 (s, 2H), 5.45 (d, J=2.1, 1H), 5.21 (s, 1H), 5.04 (s, 1H), 4.04-3.73 (m, 5H), 3.13-3.05 (m, 1H), 2.28-2.21 (m, 2H), 2.10-1.98 (m, 2H), 1.97-1.87 (m, 1H), 1.82-1.72 (m, 1H).

Example 68

5-(4-Cyclobutyl-2-fluoro-3-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}phenyl)pyrazin-2-amine Step A

tert-Butyl 4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}piperidine-1-carboxylate (50 mg, 0.11 mmol) was dissolved in formic acid (1 mL) and treated with 2 eq. of 6 N HCl (aq). The mixture was allowed to stir for 2 hours and then concentrated to give the bis-HCl salt. The crude product was triturated with acetonitrile and then purified by HPLC to give 5-(4-cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl)pyrazin-2-amine (46 mg, 98%).

Step B

5-(4-Cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl)pyrazin-2-amine was dissolved in pyridine (0.32 mL) and treated with a solution of methanesulfonyl chloride (10 mg, 0.11 mmol) in DCM (0.25 mL). The reaction was stirred at room temperature for 18 hours before concentrating to dryness. The crude product was purified by FCC to afford the title compound (6 mg, 10%). MS (ESI): mass calcd. for C₂₁H₂₇FN₄O₃S, 434.18; m/z found, 435.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.38 (m, 1H), 8.20 (d, J=1.4, 1H), 7.60-7.53 (m, 1H), 7.16 (d, J=8.2, 1H), 3.89 (t, J=7.8, 3H), 3.84-3.72 (m, 1H), 2.81 (s, 3H), 2.75 (m, 2H), 2.40-2.28 (m, 2H), 2.23-1.84 (m, 8H), 1.62-1.48 (m, 2H).

Example 69

5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

A suspension of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (25 mg, 0.096 mmol), 2-chloro-4-methylpyrimidine (14 mg, 0.11 mmol), and K₂CO₃ (27 mg, 0.19 mmol) in DMSO (2 mL) was heated at 100° Celsius for 16 hours. The reaction was then cooled to room temperature, filtered, and the filtrate directly subjected to HPLC purification to give 5-{4-cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine (15 mg, 45%). MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.37-8.33 (m, 1H), 8.26 (d, J=1.9, 2H), 7.81-7.75 (m, 1H), 7.26 (d, J=8.3, 1H), 7.00-6.97 (m, 1H), 3.75-3.63 (m, 1H), 2.52 (d, J=2.0, 3H), 2.27-2.09 (m, 4H), 2.04-1.92 (m, 1H), 1.87-1.76 (m, 1H).

Example 70

5-{4-Cyclobutyl-2-fluoro-3-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole. MS (ESI): mass calcd. for C₁₈H₁₈FN₅O₂, 355.14; m/z found, 356.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.46 (m, 1H), 8.09 (d, J=1.4, 1H), 7.61 (m, 1H), 7.16 (d, J=8.2, 1H), 5.15 (s, 2H), 4.72 (s, 2H), 3.91-3.79 (m, 1H), 2.65 (s, 3H), 2.39-2.27 (m, 2H), 2.20-1.96 (m, 3H), 1.92-1.79 (m, 1H).

Example 71

5-[4-Cyclobutyl-3-(cyclohexylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and cyclohexylmethyl bromide. MS (ESI): mass calcd. for C₂₁H₂₆FN₃O, 355.21; m/z found, 356.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (s, 1H), 8.08 (d, J=1.4, 1H), 7.54-7.48 (m, 1H), 7.14 (d, J=8.2, 1H), 4.66 (s, 2H), 3.88-3.77 (m, 3H), 2.35 (m, 2H), 2.21-1.99 (m, 3H), 1.96-1.75 (m, 6H), 1.74-1.68 (m, 1H), 1.39-1.05 (m, 5H).

Example 72

5-[4-Cyclobutyl-3-(cyclopropylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and cyclopropylmethyl bromide. MS (ESI): mass calcd. for C₁₈H₂₀FN₃O, 313.16; m/z found, 314.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.44 (m, 1H), 8.08 (d, J=1.5, 1H), 7.56-7.49 (m, 1H), 7.15 (d, J=8.3, 1H), 4.65 (s, 2H), 3.95-3.83 (m, 3H), 2.42-2.32 (m, 2H), 2.23-1.98 (m, 3H), 1.93-1.81 (m, 1H), 1.34-1.23 (m, 1H), 0.65-0.58 (m, 2H), 0.36-0.29 (m, 2H).

Example 73

Ethyl 5-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylate

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and ethyl 5-(chloromethyl)-2-furancarboxylate. MS (ESI): mass calcd. for C₂₂H₂₂FN₃O₄, 411.16; m/z found, 412.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 8.09 (d, J=1.4, 1H), 7.60-7.53 (m, 1H), 7.17-7.11 (m, 2H), 6.50 (d, J=3.4, 1H), 5.09 (s, 2H), 4.71 (s, 2H), 4.38 (q, J=7.1, 2H), 3.83-3.70 (m, 1H), 2.35-2.25 (m, 2H), 2.16-1.95 (m, 3H), 1.90-1.79 (m, 1H), 1.39 (t, J=7.1, 3H).

Example 74

tert-Butyl 4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}piperidine-1-carboxylate

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. MS (ESI): mass calcd. for C₂₅H₃₃FN₄O₃, 456.25; m/z found, 457.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.09 (d, J=1.4, 1H), 7.59-7.46 (m, 1H), 7.15 (d, J=8.3, 1H), 4.65 (s, 2H), 4.31-4.10 (m, 2H), 3.92-3.73 (m, 3H), 2.92-2.63 (m, 2H), 2.42-2.27 (m, 2H), 2.24-1.93 (m, 4H), 1.94-1.80 (m, 3H), 1.47 (s, 9H), 1.44-1.21 (m, 2H).

Example 75

5-{4-Cyclobutyl-2-fluoro-3-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole. MS (ESI): mass calcd. for C₁₈H₁₈FN₅O₂, 355.14; m/z found, 356.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd, J=2.4, 1.6, 1H), 8.09 (d, J=1.5, 1H), 7.66-7.58 (m, 1H), 7.17 (d, J=8.1, 1H), 5.26 (s, 2H), 4.67 (s, 2H), 3.89-3.77 (m, 1H), 2.46 (s, 3H), 2.39-2.29 (m, 2H), 2.21-1.98 (m, 3H), 1.92-1.81 (m, 1H).

Example 76

5-(4-Cyclobutyl-2-fluoro-3-{[2-methoxy-5-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 2-methoxy-5-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd. for C₂₂H₂₁F₆N₃O₂S, 505.13; m/z found, 506.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50-8.46 (m, 1H), 8.10 (d, J=1.5, 1H), 8.03 (d, J=2.8, 1H), 7.72 (dd, J=9.0, 2.8, 1H), 7.61-7.54 (m, 1H), 7.16 (d, J=8.2, 1H), 6.90 (d, J=9.0, 1H), 5.11 (s, 2H), 4.65 (s, 2H), 3.88 (s, 3H), 3.85-3.73 (m, 1H), 2.33-2.23 (m, 2H), 2.20-2.08 (m, 2H), 2.06-1.91 (m, 2H), 1.91-1.78 (m, 1H).

Example 77

5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-5-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 2-fluoro-5-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd. for C₂₁H₁₈F₇N₃OS, 493.10 m/z found, 494.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.46 (m, 1H), 8.13-8.08 (m, 2H), 7.76 (m, 1H), 7.63-7.57 (m, 1H), 7.21-7.14 (m, 2H), 5.17 (s, 2H), 4.69 (s, 2H), 3.82-3.72 (m, 1H), 2.33-2.24 (m, 2H), 2.21-2.09 (m, 2H), 2.08-1.95 (m, 1H), 1.90-1.80 (m, 1H).

Example 78

5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-4-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 2-fluoro-4-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd. for C₂₁H₁₈F₇N₃OS, 493.10; m/z found, 494.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50-8.45 (m, 1H), 8.10 (d, J=1.5, 1H), 7.79 (m, 1H), 7.66-7.58 (m, 2H), 7.53 (dd, J=9.9, 2.1, 1H), 7.18 (d, J=8.2, 1H), 5.15 (s, 2H), 4.67 (s, 2H), 3.78 (p, J=8.7, 1H), 2.34-2.25 (m, 2H), 2.21-2.10 (m, 2H), 2.09-1.96 (m, 2H), 1.91-1.81 (m, 1H).

Example 79

5-(4-Cyclobutyl-2-fluoro-3-{[4-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 4-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd. for C₂₁H₁₉F₆N₃OS, 475.11 m/z found, 476.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.46 (m, 1H), 8.10 (d, J=1.5, 1H), 7.80 (d, J=8.7, 2H), 7.62-7.55 (m, 3H), 7.18 (d, J=8.1, 1H), 5.10 (s, 2H), 4.65 (s, 2H), 3.78 (p, J=8.7, 1H), 2.34-2.25 (m, 2H), 2.22-2.09 (m, 2H), 2.09-1.95 (m, 1H), 1.91-1.81 (m, 1H).

Example 80

5-(4-Cyclobutyl-2-fluoro-3-{[3-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 3-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd. for C₂₁H₁₉F₆N₃OS, 475.11; m/z found, 476.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (dd, J=2.2, 1.6, 1H), 8.10 (d, J=1.5, 1H), 7.91 (s, 1H), 7.74 (d, J=8.2, 1H), 7.59 (dd, J=15.1, 7.3, 2H), 7.50 (m, 1H), 7.17 (d, J=8.1, 1H), 5.12 (s, 2H), 4.67 (s, 2H), 3.82-3.71 (m, 1H), 2.33-2.24 (m, 2H), 2.21-2.08 (m, 2H), 2.08-1.95 (m, 1H), 1.91-1.80 (m, 1H).

Example 81

5-(4-Cyclobutyl-2-fluoro-3-{[2-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 2-(pentafluorousulfur)benzyl bromide. MS (ESI): mass calcd. for C₂₁H₁₉F₆N₃OS, 475.11; m/z found, 476.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.46 (m, 1H), 8.10 (d, J=1.4, 1H), 7.91 (s, 1H), 7.74 (d, J=8.3, 1H), 7.64-7.56 (m, 2H), 7.50 (m, 1H), 7.17 (d, J=8.2, 1H), 5.12 (s, 2H), 4.66 (s, 2H), 3.76 (p, J=8.7, 1H), 2.33-2.24 (m, 2H), 2.20-2.08 (m, 2H), 2.07-1.94 (m, 1H), 1.91-1.79 (m, 1H).

Example 82

5-[4-Cyclobutyl-3-(cyclobutylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and cyclobutylmethyl bromide. MS (ESI): mass calcd. for C₁₉H₂₂FN₃O, 327.17; m/z found, 328.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd, J=2.2, 1.6, 1H), 8.08 (d, J=1.5, 1H), 7.51 (dd, J=13.7, 6.1, 1H), 7.14 (d, J=8.0, 1H), 4.70 (s, 2H), 4.00 (dd, J=6.8, 0.9, 2H), 3.88-3.78 (m, 1H), 2.86-2.74 (m, 1H), 2.39-2.30 (m, 2H), 2.22-1.81 (m, 11H).

Example 83

5-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-pyrazin-2-amine

5-[3-(Benzyloxy)-4-chloro-2-fluorophenyl]pyrazin-2-amine (59 mg, 0.18 mmol), 2-dicyclohexylphosphino-2′, 6′-dimethoxy-1, 1′-biphenyl (6 mg, 0.01 mmol) and palladium acetate (2 mg, 0.009 mmol) were added to a vial. The vial was capped, evacuated and back-filled with N₂. Cyclobutylzinc bromide (0.5 M solution in THF; 0.54 mL, 0.27 mmol) was added and the mixture heated at 65° Celsius for 18 hours. The reaction mixture was concentrated to dryness and the residue subjected to FCC. Further purification by HPLC and prep TLC gave the title compound (6 mg, 10%). MS (ESI): mass calcd. for C₂₁H₂₀FN₃O, 349.16; m/z found, 350.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.52-8.47 (m, 1H), 8.10 (d, J=1.5, 1H), 7.59-7.53 (m, 1H), 7.51-7.46 (m, 2H), 7.44-7.32 (m, 3H), 7.16 (d, J=8.1, 1H), 5.05 (s, 2H), 4.65 (s, 2H), 3.79 (p, J=8.7, 1H), 2.34-2.23 (m, 2H), 2.19-2.07 (m, 2H), 2.06-1.93 (m, 1H), 1.90-1.78 (m, 1H).

Example 84

4-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}benzoic Acid

To a 5 mL vial containing a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol) and 4-(2-bromoethyl)benzoic acid (49 mg, 0.21 mmol) were added KOt-Bu (37 mg, 0.42 mmol) and DMSO (0.5 mL). The resultant mixture was stirred at rt for 15 hours. The mixture was passed through a syringe filter and the filtrate subjected to HPLC purification to afford the title compound (10 mg, 13%). MS (ESI): mass calcd. for C₂₃H₂₂FN₃O₃, 407.16; m/z found, 408.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 8.18 (s, 1H), 8.03 (d, J=8.2, 2H), 7.51 (m, 1H), 7.41 (d, J=8.2, 2H), 7.13 (d, J=8.0, 1H), 4.26 (t, J=6.6, 2H), 3.61-3.48 (m, 1H), 3.18 (t, J=6.7, 2H), 2.23-2.00 (m, 4H), 1.98-1.74 (m, 2H).

Example 85

5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylic Acid

Ethyl 5-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylate (48 mg, 0.12 mmol) was dissolved in THF (2 mL) and treated with aqueous LiOH (1.0 N, 0.5 mL). The mixture was stirred at rt for 15 hours. The reaction mixture was purified using HPLC to afford the title compound. MS (ESI): mass calcd. for C₂₀H₁₈FN₃O₄, 383.13; m/z found, 384.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.22-8.15 (m, 2H), 7.50-7.43 (m, 1H), 7.08 (m, 2H), 6.43 (d, J=3.4, 1H), 5.00 (s, 2H), 2.27-2.16 (m, 2H), 2.07-1.89 (m, 3H), 1.80-1.70 (m, 1H).

Example 86

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-4-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-6-methylpyrimidin-4-amine. MS (ESI): mass calcd. for C₁₉H₁₉FN₆O, 366.16; m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.29-8.24 (m, 1H), 8.08 (d, J=1.5, 1H), 7.81 (m, 1H), 7.31 (d, J=8.2, 1H), 6.32 (d, J=0.9, 1H), 3.73-3.63 (m, 1H), 2.45 (s, 3H), 2.32-2.18 (m, 4H), 2.12-2.02 (m, 1H), 1.94-1.82 (m, 1H).

Example 87

5-{4-Cyclobutyl-2-fluoro-3-[(4-phenylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-phenylpyrimidine. MS (ESI): mass calcd. for C₂₄H₂₀FN₅O, 413.17; m/z found, 414.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 8.57 (d, J=5.0, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 8.06-8.01 (m, 2H), 7.89 (t, J=7.9, 1H), 7.54-7.45 (m, 4H), 7.29 (d, J=8.3, 1H), 3.82-3.70 (m, 1H), 2.28-2.13 (m, 4H), 2.03-1.92 (m, 1H), 1.86-1.75 (m, 1H).

Example 88

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfanyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-(methylthio)pyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅OS, 383.12; m/z found, 384.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.24-8.18 (m, 3H), 7.78 (m, 1H), 7.30 (d, J=8.2, 1H), 7.09 (d, J=5.5, 1H), 3.73-3.58 (m, 1H), 2.32 (s, 3H), 2.24-2.13 (m, 4H), 2.04-1.92 (m, 1H), 1.87-1.77 (m, 1H).

Example 89

5-{4-Cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4,6-dimethylpyrimidine. MS (ESI): mass calcd. for C₂₀H₂₀FN₅O, 365.16; m/z found, 366.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=1.2, 1H), 8.21 (s, 1H), 7.86-7.78 (m, 1H), 7.25 (d, J=8.4, 1H), 6.80 (s, 1H), 3.77-3.65 (m, 1H), 2.41 (s, 6H), 2.27-2.08 (m, 4H), 2.02-1.91 (m, 1H), 1.85-1.75 (m, 1H).

Example 90

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-isopropylpyrimidine. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O, 379.18; m/z found, 380.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.56-8.51 (m, 1H), 8.31 (d, J=1.4, 1H), 8.26 (s, 1H), 7.82 (m, 1H), 7.41-7.38 (m, 1H), 7.29 (d, J=8.4, 1H), 3.79-3.66 (m, 1H), 3.41-3.38 (m, 1H), 2.26-2.10 (m, 4H), 2.07-1.94 (m, 1H), 1.89-1.79 (m, 1H), 1.52 (s, 6H).

Example 91

5-{4-Cyclobutyl-2-fluoro-3-[(4-thiophen-2-ylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-(thiophen-2-yl)pyrimidine. MS (ESI): mass calcd. for C₂₂H₁₈FN₅OS, 419.12; m/z found, 420.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=5.3, 1H), 8.42-8.37 (m, 1H), 8.08 (d, J=1.4, 1H), 7.81-7.71 (m, 2H), 7.54-7.51 (m, 1H), 7.34 (d, J=3.2, 1H), 7.26 (d, J=8.3, 1H), 7.16-7.12 (m, 1H), 3.80-3.66 (m, 1H), 2.29-2.10 (m, 4H), 2.03-1.90 (m, 1H), 1.85-1.75 (m, 1H).

Example 92

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carbonitrile

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloropyrimidine-4-carbonitrile. ¹H NMR (400 MHz, CDCl₃) δ 8.76 (d, J=4.9, 5H), 8.71 (d, J=1.5, 5H), 8.47 (d, J=6.0, 4H), 7.97 (s, 4H), 7.93-7.82 (m, 11H), 3.74-3.61 (m, 7H), 2.25-2.10 (m, 23H), 2.03-1.91 (m, 7H), 1.81 (d, J=8.1, 6H).

Example 93

5-{4-Cyclobutyl-2-fluoro-3-[(4-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-methoxypyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂, 367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.45 (m, 1H), 8.18 (d, J=5.7, 1H), 8.08 (d, J=1.5, 1H), 7.82-7.74 (m, 1H), 7.22 (d, J=8.3, 1H), 6.47 (d, J=5.7, 1H), 3.93 (s, 3H), 3.76-3.66 (m, 1H), 2.26-2.12 (m, 4H), 2.03-1.91 (m, 1H), 1.86-1.77 (m, 1H).

Example 94

5-{4-Cyclobutyl-2-fluoro-3-[(5-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-5-methoxypyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂, 367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29-8.20 (m, 4H), 7.80-7.73 (m, 1H), 7.25 (d, J=8.2, 1H), 3.90 (s, 3H), 3.75-3.63 (m, 1H), 2.27-2.09 (m, 4H), 2.03-1.93 (m, 1H), 1.85-1.76 (m, 1H).

Example 95

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-(methylsulfonyl)pyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₃S, 415.11; m/z found, 416.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.87 (d, J=4.8, 1H), 8.44 (s, 1H), 8.09 (d, J=1.4, 1H), 7.86-7.81 (m, 1H), 7.72 (d, J=4.8, 1H), 7.24 (s, 1H), 4.70 (s, 2H), 3.73-3.63 (m, 1H), 3.20 (s, 3H), 2.27-2.08 (m, 4H), 2.03-1.93 (m, 1H), 1.86-1.78 (m, 1H).

Example 96

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-2-amine

A suspension of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol), 4-chloro-6-methylpyrimidin-2-amine (30 mg, 0.20 mmol), K₂CO₃ (53 mg, 0.39 mmol), and 18-crown-6 (3 mg, 0.01 mmol) in DMSO (2 mL) was heated for 16 hours at 140° Celsius. The reaction was then cooled to room temperature, filtered, and the filtrate directly subjected to HPLC purification to give 4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-2-amine (12 mg, 16%). MS (ESI): mass calcd. for C₁₉H₁₉FN₆O, 366.16; m/z found, 367.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.22 (m, 1H), 8.11 (d, J=1.5, 1H), 7.78 (m, 1H), 7.29 (d, J=8.3, 1H), 6.67 (d, J=0.8, 1H), 3.68-3.55 (m, 1H), 2.51 (d, J=0.7, 3H), 2.31-2.13 (m, 4H), 2.11-1.98 (m, 1H), 1.91-1.81 (m, 1H).

Example 97

5-{4-Cyclobutyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂, 367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.46 (m, 1H), 8.43-8.42 (m, 1H), 8.09-8.08 (m, 1H), 7.82-7.78 (m, 1H), 7.23-7.21 (m, 1H), 6.26-6.25 (m, 1H), 4.67 (s, 2H), 4.00 (s, 3H), 3.64-3.57 (m, 1H), 2.25-2.11 (m, 4H), 2.01-1.92 (m, 1H), 1.84-1.78 (m, 1H).

Example 98

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol

Title compound was obtained as a side product from the reaction described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O₂, 353.13; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.30 (m, 1H), 8.15-8.13 (m, 1H), 8.00-7.98 (m, 1H), 7.78-7.73 (m, 1H), 7.54-7.52 (m, 1H), 7.28-7.24 (m, 1H), 5.73 (s, 1H), 3.67-3.61 (m, 1H), 2.34-2.25 (m, 2H), 2.24-2.14 (m, 2H), 2.09-1.99 (m, 1H), 1.91-1.82 (s, 1H).

Example 99

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methoxypyrimidin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidin-2-amine. MS (ESI): mass calcd. for C₁₉H₁₉FN₆O₂, 382.15; m/z found, 383.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.26-8.21 (m, 2H), 7.81-7.74 (m, 1H), 7.31-7.26 (m, 1H), 5.67 (s, 1H), 3.93 (s, 3H), 3.67-3.57 (m, 1H), 2.30-2.13 (m, 4H), 2.08-1.97 (m, 1H), 1.89-1.80 (m, 1H).

Example 100

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methoxypyrimidin-4-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 6-chloro-2-methoxypyrimidin-4-amine. MS (ESI): mass calcd. for C₁₉H₁₉FN₆O₂, 382.15; m/z found, 383.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.18 (m, 2H), 7.82 (CDCl₃, 1H), 7.33 (d, J=8.3, 1H), 5.69 (d, J=8.6, 1H), 3.86 (d, J=8.8, 3H), 3.71-3.59 (m, 1H), 2.32-2.15 (m, 4H), 2.10-2.00 (m, 1H), 1.87 (t, J=9.0, 1H).

Example 101

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzonitrile

To a 5 mL vial containing a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol) and 4-fluorobenzonitrile (26 mg, 0.21 mmol) were added Cs₂CO₃ (96 mg, 0.29 mmol) and 0.55 mL DMSO. The resultant mixture was stirred at 80° Celsius for approximately 15 hours. The mixture was cooled to room temperature and then passed through a syringe filter. The filtrate was subjected to FCC to give the title compound (36 mg, 52%). MS (ESI): mass calcd. for C₂₁H₁₇FN₄O, 360.14; m/z found, 361.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.42 (m, 1H), 8.11-8.08 (d, J=1.5, 1H), 7.85-7.78 (m, 1H), 7.63-7.56 (m, 2H), 7.29-7.23 (m, 1H), 6.97-6.90 (m, 2H), 4.77-4.66 (s, 2H), 3.63-3.51 (m, 1H), 2.26-2.07 (m, 4H), 2.03-1.89 (m, 1H), 1.87-1.76 (m, 1H).

Example 102

5-(4-Cyclobutyl-2-fluor-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 2-fluoro-6-(trifluoromethyl)pyridine. MS (ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (dd, J=2.4, 1.6, 1H), 8.09 (d, J=1.5, 1H), 7.84 (dd, J=11.7, 4.0, 1H), 7.81-7.75 (m, 1H), 7.37 (d, J=7.3, 1H), 7.23 (d, J=8.1, 1H), 7.12 (d, J=8.4, 1H), 4.65 (s, 2H), 3.64 (p, J=8.8, 1H), 2.23-2.07 (m, 4H), 2.00-1.87 (m, 1H), 1.85-1.74 (m, 1H).

Example 103

Methyl 4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoate

The title compound was prepared using conditions similar to those described in Example 101 using methyl 4-fluorobenzoate. MS (ESI): mass calcd. for C₂₂H₂₀FN₃O₃, 393.15; m/z found, 394.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=1.2, 1H), 8.19 (d, J=1.0, 1H), 8.03-7.96 (m, 2H), 7.87 (m, 1H), 7.30 (d, J=8.4, 1H), 6.88 (d, J=8.8, 2H), 3.90 (s, 3H), 3.68-3.57 (m, 1H), 2.26-2.06 (m, 4H), 2.02-1.88 (m, 1H), 1.86-1.75 (m, 1H)

Example 104

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 2-chloro-5-(trifluoromethyl)-pyrimidine. MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=0.6, 2H), 8.48-8.43 (m, 1H), 8.09 (d, J=1.5, 1H), 7.88-7.79 (m, 1H), 7.25 (d, J=8.3, 1H), 4.76 (s, 2H), 3.67 (p, J=8.9, 1H), 2.27-2.08 (m, 4H), 2.05-1.90 (m, 1H), 1.88-1.76 (m, 1H).

Example 105

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 2-chloro-5-(trifluoromethyl)pyrazine. MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=0.9, 1H), 8.47-8.43 (m, 1H), 8.41 (d, J=0.4, 1H), 8.09 (d, J=1.5, 1H), 7.84 (m, 1H), 7.25 (d, J=8.7, 1H), 4.71 (s, 2H), 3.60 (p, J=8.8, 1H), 2.26-2.08 (m, 4H), 2.05-1.91 (m, 1H), 1.89-1.75 (m, 1H).

Example 106

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridazin-3-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 3-chloro-6-trifluoromethyl-pyridazine. MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.43 (m, 1H), 8.08 (d, J=1.4, 1H), 7.88-7.79 (m, 2H), 7.43 (d, J=9.1, 1H), 7.23 (d, J=8.3, 1H), 4.67 (s, 2H), 3.68-3.56 (m, 1H), 2.24-2.14 (m, 4H), 2.03-1.89 (m, 1H), 1.87-1.77 (m, 1H).

Example 107

Methyl 6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylate

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 6-fluoronicotinic acid methyl ester. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₃, 394.14; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.77 (dd, J=2.3, 0.5, 1H), 8.46 (s, 1H), 8.31 (dd, J=8.6, 2.3, 1H), 8.08 (d, J=1.3, 1H), 7.83-7.76 (m, 1H), 7.23 (d, J=8.3, 1H), 7.04 (dd, J=8.6, 0.6, 1H), 4.68 (s, 2H), 3.91 (s, 3H), 3.67-3.55 (m, 1H), 2.23-2.07 (m, 4H), 2.00-1.87 (m, 1H), 1.85-1.75 (m, 1H).

Example 108

5-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 2-cyano-5-fluoropyridine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=2.8, 1H), 8.45-8.41 (m, 1H), 8.10 (d, J=1.5, 1H), 7.88-7.81 (m, 1H), 7.63 (d, J=8.6, 1H), 7.28 (d, J=7.7, 1H), 7.19-7.12 (m, 1H), 4.79 (s, 2H), 3.58 (p, J=8.8, 1H), 2.26-2.07 (m, 4H), 2.05-1.91 (m, 1H), 1.89-1.78 (m, 1H).

Example 109

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 using 4-chloro-pyridine-2-carbonitrile. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J=5.7, 1H), 8.47-8.43 (m, 1H), 8.10 (d, J=1.2, 1H), 7.88 (m, 1H), 7.32-7.25 (m, 1H), 7.22 (d, J=2.3, 1H), 6.99 (dd, J=5.7, 2.4, 1H), 4.74 (s, 2H), 3.54 (p, J=8.9, 1H), 2.25-2.08 (m, 4H), 2.05-1.92 (m, 1H), 1.89-1.79 (m, 1H).

Example 110

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 using 3-cyano-2-fluoropyridine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48-8.44 (m, 1H), 8.29 (dd, J=5.0, 1.9, 1H), 8.09 (d, J=1.5, 1H), 8.03 (dd, J=7.6, 1.9, 1H), 7.86-7.78 (m, 1H), 7.23 (d, J=8.3, 1H), 7.11 (dd, J=7.6, 5.0, 1H), 4.66 (s, 2H), 3.65 (p, J=8.9, 1H), 2.29-2.11 (m, 4H), 2.06-1.92 (m, 1H), 1.87-1.76 (m, 1H).

Example 111

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 using 2-cyano-6-fluoropyridine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (dd, J=2.2, 1.6, 1H), 8.10 (d, J=1.5, 1H), 7.86-7.76 (m, 2H), 7.42 (dd, J=7.3, 0.7, 1H), 7.25-7.19 (m, 2H), 4.69 (s, 2H), 3.59 (p, J=8.9, 1H), 2.22-2.09 (m, 4H), 1.99-1.87 (m, 1H), 1.86-1.76 (m, 1H).

Example 112

3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 using 2-cyano-3-fluoropyridine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (dd, J=2.2, 1.6, 1H), 8.39 (dd, J=4.5, 1.2, 1H), 8.10 (d, J=1.5, 1H), 7.89-7.80 (m, 1H), 7.39 (dd, J=8.7, 4.5, 1H), 7.28 (d, J=7.2, 1H), 7.02 (m, 1H), 4.78 (s, 2H), 3.69-3.58 (m, 1H), 2.31-2.09 (m, 4H), 2.07-1.94 (m, 1H), 1.89-1.78 (m, 1H).

Example 113

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and 2-fluoro-5-(trifluoromethyl)pyridine. MS (ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.40 (s, 1H), 8.08 (d, J=1.4, 1H), 7.93 (dd, J=8.7, 2.3, 1H), 7.80 (m, 1H), 7.23 (d, J=8.3, 1H), 7.12 (d, J=8.7, 1H), 4.70 (s, 2H), 3.61 (p, J=8.9, 1H), 2.25-2.08 (m, 4H), 2.00-1.89 (m, 1H), 1.86-1.75 (m, 1H).

Example 114

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and using 5-cyano-2-fluoropyridine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.41 (m, 2H), 8.09 (d, J=1.5, 1H), 7.96 (dd, J=8.6, 2.3, 1H), 7.84-7.78 (m, 1H), 7.23 (d, J=8.3, 1H), 7.13 (dd, J=8.6, 0.6, 1H), 4.70 (s, 2H), 3.58 (p, J=8.9, 1H), 2.23-2.08 (m, 4H), 2.02-1.89 (m, 1H), 1.86-1.75 (m, 1H).

Example 115

5-{4-Cyclobutyl-2-fluoro-3-[4-(pentafluoro-lambda˜6˜-sulfanyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 130° Celsius via microwave irradiation for 1 hour and using 4-fluorophenylsulfur pentafluoride. MS (ESI): mass calcd. for C₂₀H₁₇F₆N₃OS, 461.10; m/z found, 462.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=1.2, 1H), 8.21 (s, 1H), 7.87 (m, 1H), 7.73-7.65 (m, 2H), 7.34-7.27 (m, 1H), 6.89 (d, J=8.9, 2H), 3.90 (s, 2H), 3.68-3.56 (m, 1H), 2.30-2.19 (m, 2H), 2.19-2.09 (m, 2H), 2.06-1.92 (m, 1H), 1.89-1.75 (m, 1H).

Example 116

5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 130° Celsius via microwave irradiation for 1 hour and using 4-fluorophenyl methyl sulfone. MS (ESI): mass calcd. for C₂₁H₂₀FN₃O₃S, 413.12; m/z found, 414.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=1.2, 1H), 8.18 (s, 1H), 7.94-7.84 (m, 3H), 7.31 (d, J=8.4, 1H), 7.00 (d, J=8.8, 2H), 3.61 (p, J=8.9, 1H), 3.08 (s, 3H), 2.29-2.07 (m, 4H), 2.05-1.91 (m, 1H), 1.88-1.77 (m, 1H).

Example 117

5-{4-Cyclobutyl-2-fluoro-3-[2-(methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-fluorophenylmethylsulfone. MS (ESI): mass calcd. for C₂₁H₂₀FN₃O₃S, 413.12; m/z found, 414.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.44-8.41 (m, 1H), 8.11-8.06 (m, 2H), 7.87-7.80 (m, 1H), 7.46 (m, 1H), 7.33 (d, J=8.3, 1H), 7.18 (m, 1H), 6.64 (d, J=8.4, 1H), 4.74 (s, 2H), 3.73 (p, J=8.7, 1H), 3.38 (s, 3H), 2.45-2.33 (m, 1H), 2.29-2.16 (m, 1H), 2.12-1.90 (m, 3H), 1.86-1.75 (m, 1H).

Example 118

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-bromopyrimidine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13 m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=4.8, 2H), 8.49-8.45 (m, 1H), 8.09 (d, J=1.5, 1H), 7.83-7.77 (m, 1H), 7.24 (d, J=8.2, 1H), 7.83-7.78 (m, 1H), 4.66 (s, 2H), 3.70 (p, J=8.8, 1H), 2.27-2.08 (m, 4H), 2.03-1.89 (m, 1H), 1.85-1.75 (m, 1H).

Example 119

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine Method 1:

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 2 hours and using 4-amino-2-chloropyrimidine.

Method 2:

A mixture of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (17.0 g, 65.6 mmol), K₂CO₃ (13.6 g, 98.4 mmol), 2-chloropyrimidin-4-amine (8.9 g, 69 mmol), 18-crown-6 (0.87 g, 3.3 mmol), and DMA (131 mL) was stirred at 120° Celsius for 15 hours. Water (306 mL) was added, and the reaction mixture cooled to room temperature. Solid precipitate was collected by vacuum filtration and dried in a vacuum oven at 70° Celsius to give the crude product (23.1 g, 100%). The solid was recrystallized from EtOH and treated successively with activated charcoal and silica-supported thiol to remove residual Pd and afford the title compound (13.0 g, 56%). MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.25 (s, 1H), 8.01 (d, J=1.5, 1H), 7.83 (d, J=5.8, 1H), 7.66 (m, 1H), 7.23 (d, J=8.3, 1H), 7.06 (s, 2H), 6.67 (s, 2H), 6.17 (d, J=5.8, 1H), 3.60-3.47 (m, 1H), 2.19-2.01 (m, 4H), 1.98-1.85 (m, 1H), 1.80-1.68 (m, 1H).

Example 120

5-{3-[3,4-Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation 1 hour and using 3,4-bis-(trifluoromethyl)fluorobenzene. MS (ESI): mass calcd. for C₂₂H₁₆F₇N₃O, 471.12; m/z found, 472.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (dd, J=2.2, 1.6, 1H), 8.09 (d, J=1.5, 1H), 7.89-7.82 (m, 1H), 7.74 (d, J=8.8, 1H), 7.42 (d, J=2.5, 1H), 7.29 (d, J=8.3, 1H), 7.00 (dd, J=8.8, 2.1, 1H), 4.76 (s, 2H), 3.59 (p, J=8.8, 1H), 2.27-2.07 (m, 4H), 2.05-1.91 (m, 1H), 1.88-1.76 (m, 1H).

Example 121

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-fluoro-3-(trifluoromethyl)pyridine. MS (ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (s, 1H), 8.24 (d, J=3.7, 1H), 8.08 (s, 1H), 8.01 (d, J=7.7, 1H), 7.80 (m, 1H), 7.23 (d, J=8.4, 1H), 7.13-7.06 (m, 1H), 4.62 (s, 2H), 3.71-3.60 (m, 1H), 2.28-2.05 (m, 4H), 2.01-1.89 (m, 1H), 1.84-1.74 (m, 1H).

Example 122

5-{3-[(3-Chloropyridin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 3-chloro-2-fluoropyridine. MS (ESI): mass calcd. for C₁₉H₁₆ClFN₄O, 370.10; m/z found, 371.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.00 (d, J=1.5, 1H), 7.82 (d, J=5.8, 1H), 7.63 (m, 1H), 7.22 (d, J=8.3, 1H), 7.04 (s, 2H), 6.65 (s, 2H), 6.17 (d, J=5.8, 1H), 2.14-2.01 (m, 4H), 1.94-1.84 (m, 1H), 1.76-1.69 (m, 1H).

Example 123

5-{3-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 2 hours and using 2-chloro-1-fluoro-4-methylsulfonylbenzene. MS (ESI): mass calcd. for C₂₁H₁₉ClFN₃O₃S, 447.08; m/z found, 448.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30-8.26 (m, 1H), 8.13 (d, J=2.3, 1H), 8.01 (d, J=1.5, 1H), 7.85-7.74 (m, 2H), 7.38 (d, J=8.3, 1H), 6.87 (dd, J=8.7, 1.1, 1H), 6.72 (s, 2H), 3.24 (s, 3H), 2.17-2.07 (m, 4H), 1.96-1.84 (m, 1H), 1.81-1.69 (m, 1H).

Example 124

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 4-chloro-2-(trifluoromethyl)pyrimidine. MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J=5.7, 1H), 8.46-8.42 (m, 1H), 8.09 (d, J=1.4, 1H), 7.84 (m, 1H), 7.24 (d, J=8.3, 1H), 7.12 (d, J=5.7, 1H), 4.74 (s, 2H), 3.64-3.52 (m, 1H), 2.24-2.08 (m, 4H), 2.05-1.90 (m, 1H), 1.87-1.77 (m, 1H).

Example 125

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 4-chloro-6-trifluoromethylpyrimidine. MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.48-8.42 (m, 1H), 8.09 (d, J=1.5, 1H), 7.91-7.82 (m, 1H), 7.38 (d, J=1.0, 1H), 7.28-7.22 (m, 1H), 4.73 (s, 2H), 3.58 (p, J=8.8, 1H), 2.27-2.09 (m, 4H), 2.05-1.91 (m, 1H), 1.88-1.76 (m, 1H).

Example 126

5-{4-Cyclobutyl-2-fluoro-3-[3-methyl-4-(methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 2 hours and using 4-fluoro-2-methyl-1-(methylsulfonyl)benzene. MS (ESI): mass calcd. for C₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.43 (m, 1H), 8.10 (d, J=1.5, 1H), 7.95 (d, J=8.8, 1H), 7.85-7.78 (m, 1H), 7.27 (d, J=9.3, 1H), 6.84 (d, J=2.5, 1H), 6.78 (dd, J=8.8, 2.6, 1H), 4.85 (s, 2H), 3.58 (p, J=8.9, 1H), 3.07 (s, 3H), 2.26-2.07 (m, 4H), 2.00-1.90 (m, 1H), 1.87-1.75 (m, 1H).

Example 127

5-(4-Cyclobutyl-2-fluoro-3-(4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloro-5-methansulfonylbenzotrifluoride. MS (ESI): mass calcd. for C₂₂H₁₉F₄N₃O₃S, 481.11; m/z found, 482.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.41 (m, 1H), 8.28 (d, J=2.2, 1H), 8.09 (d, J=1.5, 1H), 7.96 (dd, J=8.8, 2.3, 1H), 7.89-7.83 (m, 1H), 7.30 (d, J=8.3, 1H), 6.82 (d, J=8.8, 1H), 4.79 (s, 2H), 3.62 (p, J=8.8, 1H), 3.09 (s, 3H), 2.43-1.91 (m, 4H), 1.88-1.69 (m, 2H).

Example 128

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 2 hours and using 5-fluoro-2-(trifluoromethyl)pyridine. MS (ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=2.8, 1H), 8.44 (dd, J=2.2, 1.7, 1H), 8.09 (d, J=1.5, 1H), 7.86-7.80 (m, 1H), 7.60 (d, J=8.7, 1H), 7.28 (d, J=7.8, 1H), 7.19 (dd, J=8.7, 2.8, 1H), 4.78 (s, 2H), 3.61 (p, J=8.8, 1H), 2.28-2.08 (m, 4H), 2.04-1.91 (m, 1H), 1.88-1.78 (m, 1H).

Example 129

5-{4-Cyclobutyl-2-fluoro-3-[(3-methoxypyridin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-fluoro-3-methoxypyridine. MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₂, 366.15; m/z found, 367.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 8.20 (s, 1H), 7.84-7.77 (m, 1H), 7.63 (dd, J=5.0, 1.4, 1H), 7.27-7.21 (m, 2H), 6.99 (dd, J=7.9, 4.9, 1H), 4.01 (s, 3H), 3.74-3.61 (m, 1H), 2.25-2.11 (m, 4H), 2.01-1.88 (m, 1H), 1.87-1.74 (m, 1H).

Example 130

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-amino-4-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48-8.45 (m, 1H), 8.15 (d, J=5.7, 1H), 8.06 (d, J=1.5, 1H), 7.81-7.75 (m, 1H), 7.20 (d, J=8.3, 1H), 6.25 (d, J=5.7, 1H), 5.01 (s, 2H), 4.70 (s, 2H), 3.59 (p, J=8.9, 1H), 2.30-2.07 (m, 4H), 2.04-1.90 (m, 1H), 1.87-1.75 (m, 1H).

Example 131

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 2-chloro-4-(trifluoromethyl)pyrimidine. MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=4.8, 1H), 8.45 (dd, J=2.1, 1.7, 1H), 8.09 (d, J=1.5, 1H), 7.87-7.78 (m, 1H), 7.39 (d, J=4.9, 1H), 7.24 (d, J=8.3, 1H), 4.68 (s, 2H), 3.70 (p, J=8.9, 1H), 2.26-2.08 (m, 4H), 2.03-1.90 (m, 1H), 1.86-1.76 (m, 1H).

Example 132

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5-(methylsulfonyl)benzonitrile

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 2-fluoro-5-(methylsulfony)lbenzonitrile. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O₃S, 438.12; m/z found, 439.1 [M+H]⁺. ¹H NMR (400 MHz, THF-d₈) δ 8.44 (d, J=2.3, 1H), 8.39 (dd, J=2.6, 1.5, 1H), 8.08-7.96 (m, 3H), 7.37 (d, J=8.3, 1H), 6.98 (dd, J=8.9, 1.5, 1H), 6.08 (s, 2H), 3.76-3.65 (m, 1H), 3.12 (s, 3H), 2.35-2.18 (m, 4H), 2.12-1.99 (m, 1H), 1.94-1.82 (m, 1H).

Example 133

5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfonyl)-3-(trifluoromethyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 5-bromo-2-(methylsulfonyl)benzotrifluoride. MS (ESI): mass calcd. for C₂₂H₁₉F₄N₃O₃S, 481.11; m/z found, 482.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.42 (m, 1H), 8.21 (d, J=8.9, 1H), 8.10 (d, J=1.5, 1H), 7.90-7.82 (m, 1H), 7.49 (d, J=2.6, 1H), 7.29 (d, J=8.3, 1H), 7.04 (dd, J=8.9, 2.5, 1H), 4.75 (s, 2H), 3.57 (p, J=8.8, 1H), 3.18 (s, 3H), 2.27-2.09 (m, 4H), 2.05-1.92 (m, 1H), 1.89-1.78 (m, 1H).

Example 134

5-{4-Cyclobutyl-2-fluoro-3-[(2-methylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 4-chloro-2-methylpyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.43 (m, 2H), 8.09 (d, J=1.3, 1H), 7.80 (m, 1H), 7.23 (d, J=8.3, 1H), 6.70 (d, J=5.8, 1H), 4.71 (s, 2H), 3.59 (p, J=8.9, 1H), 2.55 (s, 3H), 2.25-2.07 (m, 4H), 2.03-1.89 (m, 1H), 1.87-1.72 (m, 1H).

Example 135

5-(4-Cyclobutyl-2-fluoro-3-{[2-(1-methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 2 hours and using 4-chloro-2-isopropyl-pyrimidine. MS (ESI): mass calcd. for C₂₁H₂₃FN₆O, 394.2; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J=5.7, 1H), 8.47-8.44 (m, 1H), 8.10 (d, J=1.4, 1H), 7.80 (m, 1H), 7.22 (d, J=8.3, 1H), 6.73 (d, J=5.7, 1H), 4.69 (s, 2H), 3.61 (p, J=8.8, 1H), 3.02 (hept, J=6.9, 1H), 2.24-2.06 (m, 4H), 2.03-1.88 (m, 1H), 1.86-1.75 (m, 1H), 1.19 (d, J=6.9, 6H).

Example 136

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 3 hours and using 4-amino-6-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.44 (m, 1H), 8.25 (d, J=0.6, 1H), 8.08 (d, J=1.5, 1H), 7.81-7.74 (m, 1H), 7.21 (d, J=8.2, 1H), 5.94 (d, J=0.9, 1H), 4.97 (s, 2H), 4.73 (s, 2H), 3.61 (p, J=8.8, 1H), 2.29-2.09 (m, 4H), 2.04-1.90 (m, 1H), 1.87-1.77 (m, 1H).

Example 137

5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 2 hours and using 2,4-dichloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₅ClFN₅O, 371.09; m/z found, 372.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=5.7, 1H), 8.25 (s, 1H), 8.02 (d, J=1.4, 1H), 7.77 (m, 1H), 7.37-7.29 (m, 2H), 6.70 (s, 2H), 3.55-3.43 (m, 1H), 2.17-2.00 (m, 4H), 1.98-1.83 (m, 1H), 1.81-1.68 (m, 1H).

Example 138

5-{3-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine Trifluoroacetate Salt

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 4-azetidin-1-yl-6-chloro-pyrimidine. MS (ESI): mass calcd. for C₂₁H₂₁FN₆O, 392.18; m/z found, 393.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=1.1, 1H), 8.35 (s, 1H), 8.06 (d, J=0.9, 1H), 7.87 (m, 1H), 7.24 (d, J=8.4, 1H), 5.77 (s, 1H), 4.33 (t, J=7.1, 4H), 3.57 (p, J=8.8, 1H), 2.63-2.52 (m, 2H), 2.29-2.07 (m, 4H), 2.08-1.93 (m, 1H), 1.90-1.77 (m, 1H).

Example 139

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using (6-chloro-2-trifluoromethylpyrimidin-4-yl)dimethyl-amine. MS (ESI): mass calcd. for C₂₁H₂₀F₄N₆O, 448.16; m/z found, 449.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.07 (d, J=1.4, 1H), 7.82-7.74 (m, 1H), 7.22 (d, J=8.3, 1H), 5.84 (s, 1H), 4.79 (s, 2H), 3.62 (p, J=8.9, 1H), 3.11 (s, 6H), 2.27-2.07 (m, 4H), 2.03-1.75 (m, 2H).

Example 140

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methylpyrimidin-4-amine Trifluoroacetate Salt

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 4-amino-6-chloro-2-methylpyrimidine. MS (ESI): mass calcd. for C₁₉H₁₉FN₆O, 366.16; m/z found, 367.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J=1.7, 1H), 8.11 (d, J=1.5, 1H), 7.82 (m, 1H), 7.34 (d, J=8.2, 1H), 6.03 (s, 1H), 3.69-3.57 (m, 1H), 2.48 (s, 3H), 2.33-2.13 (m, 4H), 2.12-1.97 (m, 1H), 1.92-1.81 (m, 1H).

Example 141

5-{4-Cyclobutyl-3-[(6-cyclopropylpyrimidin-4-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 4-chloro-6-cyclopropyl-pyrimidine. MS (ESI): mass calcd. for C₂₁H₂₀FN₅O, 377.16; m/z found, 378.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=0.7, 1H), 8.47 (d, J=1.8, 1H), 8.08 (d, J=1.5, 1H), 7.84-7.77 (m, 1H), 7.22 (d, J=8.3, 1H), 6.83 (d, J=1.0, 1H), 4.65 (s, 2H), 3.59 (p, J=9.0, 1H), 2.28-2.09 (m, 4H), 2.04-1.89 (m, 2H), 1.87-1.75 (m, 1H), 1.21-1.15 (m, 2H), 1.13-1.05 (m, 2H).

Example 142

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 4-chloro-6-(methoxymethyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C₂₀H₂₁FN₆O₂, 396.17; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.45 (m, 1H), 8.06 (d, J=1.5, 1H), 7.81-7.74 (m, 1H), 7.20 (d, J=8.3, 1H), 6.37 (s, 1H), 5.00 (s, 2H), 4.70 (s, 2H), 4.34 (s, 2H), 3.66-3.53 (m, 1H), 3.47 (s, 3H), 2.30-2.07 (m, 4H), 2.04-1.90 (m, 1H), 1.87-1.74 (m, 1H).

Example 143

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-chloropyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-amino-4,6-dichloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₆ClFN₆O, 386.10; m/z found, 387.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.30-8.23 (m, 2H), 7.77 (m, 1H), 7.23 (d, J=8.2, 1H), 6.29 (d, J=2.6, 1H), 3.64-3.52 (m, 1H), 2.31-2.21 (m, 2H), 2.21-2.09 (m, 2H), 2.08-1.95 (m, 1H), 1.90-1.78 (m, 1H).

Example 144

5-{4-Cyclobutyl-2-fluoro-3-[(2-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° C. via microwave irradiation for one hour and using 4-chloro-2-phenylpyrimidine. MS (ESI): mass calcd. for C₂₄H₂₀FN₅O, 413.16; m/z found, 414.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.68 (d, J=5.7, 1H), 8.50-8.46 (m, 1H), 8.24-8.18 (m, 2H), 8.09 (d, J=1.5, 1H), 7.88-7.81 (m, 1H), 7.44-7.33 (m, 3H), 7.26 (m, 1H), 6.86 (d, J=5.6, 1H), 4.71 (s, 2H), 3.63 (p, J=8.9, 1H), 2.25-2.10 (m, 4H), 1.99-1.88 (m, 1H), 1.83-1.75 (m, 1H).

Example 145

5-{4-Cyclobutyl-2-fluoro-3-[(6-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 4-chloro-6-phenylpyrimidine. MS (ESI): mass calcd. for C₂₄H₂₀FN₅O, 413.16; m/z found, 414.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.82 (d, J=1.0, 1H), 8.52-8.46 (m, 1H), 8.14-8.06 (m, 3H), 7.88-7.80 (m, 1H), 7.58-7.48 (m, 3H), 7.39 (d, J=1.0, 1H), 7.25 (d, J=8.8, 1H), 4.69 (s, 2H), 3.63 (p, J=8.9, 1H), 2.29-2.10 (m, 4H), 2.05-1.89 (m, 1H), 1.87-1.75 (m, 1H).

Example 146

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-benzylpyrimidin-4-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 6-amino-2-benzyl-4-chloropyrimidine. MS (ESI): mass calcd. for C₂₅H₂₃FN₆O, 442.19; m/z found, 443.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (m, 1H), 8.08 (m, 1H), 7.69 (t, J=7.8, 1H), 7.37 (s, 1H), 7.30-7.13 (m, 5H), 5.62 (s, 1H), 3.90 (s, 2H), 3.63-3.52 (m, 1H), 2.26-2.04 (m, 4H), 2.02-1.88 (m, 1H), 1.85-1.74 (m, 1H).

Example 147

5-(4-Cyclobutyl-2-fluoro-3-{[6-(1-methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 4-chloro-6-isopropyl-pyrimidine. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O, 379.18; m/z found, 380.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J=0.9, 1H), 8.49-8.43 (m, 1H), 8.08 (d, J=1.5, 1H), 7.84-7.78 (m, 1H), 7.23 (d, J=8.3, 1H), 6.86 (d, J=0.5, 1 H), 4.70 (s, 2H), 3.60 (p, J=8.9, 1H), 3.02 (hept, J=6.9, 1H), 2.26-2.08 (m, 4H), 2.04-1.89 (m, 1H), 1.87-1.77 (m, 1H), 1.34 (d, J=6.9, 6H).

Example 148

3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and using 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonitrile. MS (ESI): mass calcd. for C₂₀H₁₆F₄N₆O, 432.13; m/z found, 433.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (dd, J=2.2, 1.6, 1H), 8.06 (d, J=1.5, 1H), 7.91 (m, 1H), 7.30-7.20 (m, 1H), 4.76 (s, 2H), 3.95 (s, 3H), 3.74 (p, J=8.8, 1H), 2.38-2.19 (m, 4H), 2.14-1.99 (m, 1H), 1.98-1.85 (m, 1H).

Intermediate C

tert-Butyl-(2-((2-chloropyrimidin-4-yl)amino)ethyl)carbamate Intermediate D

tert-Butyl-(2-((4-chloropyrimidin-2-yl)amino)ethyl)carbamate

2,4-Dichloropyrimidine (1.0 g, 6.7 mmol), tert-butyl N-(2-aminoethyl)carbamate (1.06 mL, 6.71 mmol) and triethylamine (1.12 mL, 8.05 mmol) were partially dissolved in acetonitrile (22.5 mL). The mixture was stirred at room temperature for 14 hours before diluting with water and extracting with DCM. The DCM extract was dried over Na₂SO₄, filtered and concentrated to dryness. The crude mixture was purified by FCC to give tert-butyl-(2-((2-chloropyrimidin-4-yl)amino)ethyl)carbamate (1.07 g, 58%) and tert-butyl-(2-((4-chloropyrimidin-2-yl)amino)ethyl)carbamate (280 mg, 15%).

Example 149

tert-Butyl [2-({2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-yl}amino)ethyl]carbamate

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and Intermediate C. MS (ESI): mass calcd. for C₂₅H₃₀FN₇O₃, 495.24; m/z found, 496.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.14 (d, J=5.6, 1H), 8.07 (s, 1H), 7.73 (m, 1H), 7.19 (d, J=8.3, 1H), 6.20 (d, J=5.6, 1H), 5.51 (s, 1H), 5.03 (s, 1H), 4.81 (s, 2H), 3.66-3.53 (m, 1H), 3.25 (d, J=52.0, 4H), 2.31-2.05 (m, 4H), 2.05-1.89 (m, 1H), 1.87-1.72 (m, 1H), 1.39 (s, 9H).

Example 150

N-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}ethane-1,2-diamine

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 1 hour and Intermediate D. MS (ESI): mass calcd. for C₂₀H₂₂FN₇O, 395.19; m/z found, 396.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.30-8.25 (m, 1H), 8.05 (d, J=1.5, 1H), 7.84 (s, 1H), 7.67 (m, 1H), 7.25 (d, J=8.2, 1H), 6.25 (d, J=5.8, 1H), 3.66 (p, J=8.9, 1H), 3.26 (t, J=6.2, 2H), 2.70 (s, 2H), 2.29-2.09 (m, 4H), 2.06-1.93 (m, 1H), 1.88-1.77 (m, 1H).

Example 151

Methyl 2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylate Trifluoroacetate Salt

The title compound was prepared using conditions similar to those described in Example 101 heating at 80° Celsius via microwave irradiation for 2 hours and methyl 2-chloropyrimidine-4-carboxylate (280 mg, 15%). MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₃, 395.14; m/z found, 396.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=4.9, 1H), 8.37 (d, J=1.3, 1H), 8.11 (d, J=1.2, 1H), 7.86 (m, 1H), 7.80 (d, J=4.9, 1H), 7.30-7.24 (m, 1H), 4.67 (s, 2H), 4.04 (s, 3H), 3.76-3.63 (m, 1H), 2.27-2.07 (m, 4H), 2.04-1.88 (m, 1H), 1.87-1.74 (m, 1H).

Example 152

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylic Acid

Title compound was found as an additional product in the formation of methyl 2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylate, Example 151. MS (ESI): mass calcd. for C₁₉H₁₆FN₅O₃, 381.12; m/z found, 382.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.78 (d, J=4.9, 1H), 8.25 (d, J=1.5, 1H), 8.21 (m, 1H), 7.85-7.79 (m, 2H), 7.30 (d, J=8.3, 1H), 3.73-3.61 (m, 1H), 2.24-2.08 (m, 4H), 2.06-1.91 (m, 1H), 1.86-1.75 (m, 1H).

Example 153

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoic acid

The title compound was prepared using analogous conditions described in Example 85 using Example 103 as a starting material. MS (ESI): mass calcd. for C₂₁H₁₈FN₃O₃, 379.13; m/z found, 380.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1H), 8.16 (s, 1H), 8.03-7.97 (m, 2H), 7.78 (m, 1H), 7.35 (d, J=8.3, 1H), 6.92 (d, J=8.8, 2H), 3.69-3.57 (m, 1H), 2.24-2.11 (m, 4H), 2.04-1.90 (m, 1H), 1.88-1.76 (m, 1H).

Example 154

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylic Acid

The title compound was prepared using analogous conditions described in Example 85 using Example 107 as a starting material. MS (ESI): mass calcd. for C₂₀H₁₇FN₄O₃, 380.13; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.59-8.53 (m, 1H), 8.27 (dd, J=8.6, 2.4, 1H), 8.21-8.16 (m, 1H), 7.98 (d, J=1.5, 1H), 7.67 (m, 1H), 7.26-7.17 (m, 2H), 2.08-1.95 (m, 4H), 1.90-1.76 (m, 1H), 1.73-1.61 (m, 1H).

Example 155

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzamide

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzonitrile (30 mg, 0.083 mmol) was dissolved in TFA (0.75 mL) and treated with conc. H₂SO₄ (0.25 mL). The mixture was stirred at room temperature for 20 hours. The mixture was then poured over ice water (100 mL) and the aqueous layer extracted with 10% MeOH/DCM. The water layer was adjusted to pH 7 with aqueous NaOH and extracted again 10% MeOH/DCM. The combined organic extracts were dried and concentrated to dryness. The crude product was purified by FCC to afford the title compound (28 mg, 89%). MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₂, 378.15; m/z found, 379.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 8.05 (s, 1H), 7.89-7.83 (m, 2H), 7.77-7.70 (m, 1H), 7.33 (d, J=8.3, 1H), 6.94-6.87 (m, 2H), 3.69-3.57 (m, 1H), 2.24-2.10 (m, 4H), 2.04-1.89 (m, 1H), 1.87-1.76 (m, 1H).

Example 156

N′-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}-N,N-dimethylethane-1,2-diamine Hydrochloride

5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine (77 mg, 0.21 mmol) was partially dissolved in N,N-dimethylethylenediamine (0.23 mL) and heated via microwave irradiation at 120° Celsius for 2 hours. The reaction mixture was subjected to direct HPLC purification. The post-HPLC material was then subjected to FCC to afford the title compound. The final product was converted to the HCl salt by dissolving it in MeOH and treating the solution with HCl (1.0 M, 0.42 mL) in water. The reaction mixture was then concentrated to dryness to give the title compound (13 mg, 13%). MS (ESI): mass calcd. for C₂₂H₂₆FN₇O, 423.22; m/z found, 424.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50-8.45 (m, 1H), 8.06 (d, J=1.5, 1H), 7.93 (s, 1H), 7.79-7.71 (m, 1H), 7.20 (d, J=8.3, 1H), 6.08 (d, J=5.9, 1H), 5.74 (s, 1H), 4.69 (s, 2H), 3.78-3.65 (m, 1H), 3.37 (s, 2H), 2.51 (t, J=5.9, 2H), 2.30-2.07 (m, 11H), 2.04-1.88 (m, 1H), 1.86-1.73 (m, 1H).

Example 157

2-[3-(5-Aminopyrazin-1-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide

The title compound was prepared using conditions similar to those described in Example 160 heating for 2 hours at 80° Celsius and using Intermediate B and 2-chloropyrimidine-4-carboxamide. MS (ESI): mass calcd. for C₁₉H₁₇FN₆O₂, 380.14; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84-8.78 (d, J=4.9, 1H), 8.30-8.21 (m, 2H), 8.06-7.97 (d, J=1.5, 2H), 7.80-7.71 (m, 2H), 7.35-7.28 (d, J=8.3, 1H), 6.78-6.66 (s, 2H), 3.64-3.51 (m, 1H), 2.16-2.01 (m, 4H), 1.98-1.84 (m, 1H), 1.81-1.66 (m, 1H).

Example 158

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-5-amine

The title compound was prepared using conditions similar to those described in Example 164 heating for 18 hours at 140° Celsius using Intermediate B and 5-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.17-8.13 (m, 1H), 7.95 (d, J=1.5, 1H), 7.92 (s, 2H), 7.62-7.54 (m, 1H), 7.15 (d, J=8.3, 1H), 3.61-3.49 (m, 1H), 2.16-1.98 (m, 4H), 1.96-1.80 (m, 1H), 1.77-1.63 (m, 1H).

Example 159

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrimidin-2-amine

The title compound was prepared using analogous conditions described in Step D of Intermediate A using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 2-amino-5-bromopyrimidine. MS (ESI): mass calcd. for C₁₅H₁₆FN₃O, 273.13; m/z found, 274.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=1.4, 2H), 7.10 (d, J=8.2, 1H), 7.08-6.99 (m, 1H), 5.24 (s, 2H), 3.90 (d, J=1.4, 3H), 3.88-3.74 (m, 1H), 2.41-2.31 (m, 2H), 2.22-1.99 (m, 3H), 1.93-1.82 (m, 1H).

Intermediate E

3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol

To a 200 mL flask were added a stir bar, 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrimidin-2-amine (729 mg, 2.7 mmol) and dry DCM (27 mL). The flask was purged with nitrogen, stirred until homogeneous and cooled to −78° Celsius. The resulting solution was charged with boron tribromide (1.0 M in DCM, 8.09 mL). The mixture was kept at −78° Celsius for 30 min before warming to room temperature. After 5 hours, the reaction mixture was poured into a 500 mL mixture of ice and saturated NaHCO₃. This mixture was partitioned between EtOAc and the aqueous layer. The EtOAc layer was isolated, dried and concentrated to dryness. The resulting solid was purified by FCC to yield the title compound (602 mg, 87%). MS (ESI): mass calcd. for C₁₄H₁₄FN₃O, 259.11; m/z found, 260.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (d, J=2.0, 1H), 8.39 (d, J=1.4, 2H), 7.04 (d, J=8.0, 1H), 6.89 (m, 1H), 6.83 (s, 2H), 3.80-3.65 (m, 1H), 2.34-2.20 (m, 2H), 2.15-1.89 (m, 3H), 1.89-1.74 (m, 1H).

Example 160

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

To a 5 mL vial containing a stir bar, 3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol (80 mg, 0.31 mmol) and 2-chloropyrimidine (41 mg, 0.34 mmol) were added Cs₂CO₃ (203 mg, 0.62 mmol) and DMSO (0.8 mL). The resultant mixture was stirred at 120° Celsius for approximately 1 hour via microwave irradiation. The reaction mixture was cooled to room temperature before passing the mixture through a syringe filter and subjecting the filtrate to FCC to afford the title compound (81 mg, 78%). MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13; m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=4.8, 2H), 8.50 (d, J=1.0, 2H), 7.31-7.19 (m, 2H), 7.09-7.05 (m, 1H), 5.40 (s, 2H), 3.71 (p, J=8.9, 1H), 2.28-2.07 (m, 4H), 2.03-1.89 (m, 1H), 1.86-1.74 (m, 1H).

Example 161

5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 with DMF as the solvent heating via microwave irradiation for 2 hours and using 4-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=1.3, 2H), 8.01 (d, J=5.7, 1H), 7.25-7.16 (m, 2H), 6.17 (d, J=5.7, 1H), 5.17 (s, 2H), 5.05 (s, 2H), 3.77-3.64 (m, 1H), 2.33-2.07 (m, 4H), 2.04-1.90 (m, 1H), 1.87-1.74 (m, 1H).

Example 162

4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 heating via microwave irradiation for 2 hours and using 4-chloro-6-(methoxymethyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C₂₀H₂₁FN₆O₂, 396.17; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=1.0, 2H), 7.25-7.15 (m, 2H), 6.38 (s, 1H), 5.30 (s, 2H), 5.08 (s, 2H), 4.35 (s, 2H), 3.66-3.53 (m, 1H), 3.48 (s, 3H), 2.29-2.06 (m, 4H), 2.05-1.89 (m, 1H).

Example 163

5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 heating to 80° Celsius on a hotplate for 3 hours and using 2-chloro-4-methylpyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=1.3, 2H), 8.33 (d, J=5.0, 1H), 7.26-7.18 (m, 2H), 6.92 (d, J=5.0, 1H), 5.29 (s, 2H), 3.71 (p, J=8.9, 1H), 2.52 (s, 3H), 2.27-2.07 (m, 4H), 2.02-1.90 (m, 1H), 1.85-1.73 (m, 1H).

Example 164

5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2-amine

To a 5 mL vial containing a stir bar, 3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol (88 mg, 0.34 mmol) and 4-amino-6-chloropyrimidine (46 mg, 0.36 mmol) were added K₂CO₃ (70 mg, mg, 0.51 mmol), 18-crown-6 (9 mg, 0.03 mmol) and DMA (0.68 mL). The resultant mixture was stirred at 120° Celsius for approximately 3 hours before cooling to room temperature and passing it through a syringe filter and subjecting the filtrate to FCC to afford the title compound (42 mg, 35%). MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=1.1, 2H), 8.23 (s, 1H), 7.26-7.16 (m, 2H), 5.99 (s, 1H), 5.25 (s, 2H), 5.01 (s, 2H), 3.61 (p, J=8.9, 1H), 2.31-2.08 (m, 4H), 2.00-1.90 (m, 1H), 1.89-1.78 (m, 1H).

Example 165

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 heating to 80° Celsius for 3 hours and using 2-chloro-4-isopropyl-pyrimidine. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O, 379.180; m/z found, 380.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=1.3, 2H), 8.38 (d, J=5.1, 1H), 7.26-7.18 (m, 2H), 6.92 (d, J=5.1, 1H), 5.19 (s, 2H), 3.79-3.66 (m, 1H), 3.03-2.92 (m, 1H), 2.27-2.06 (m, 4H), 2.03-1.89 (m, 1H), 1.85-1.74 (m, 1H), 1.28 (d, J=6.9, 6H).

Example 166

4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 164 heating the reaction for 18 hours and using 2-amino-4-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=1.2, 2H), 8.16 (d, J=5.6, 1H), 7.24 (d, J=7.1, 1H), 7.19 (d, J=8.2, 1H), 6.27 (d, J=5.7, 1H), 5.19 (s, 2H), 4.98 (s, 2H), 3.65-3.54 (m, 1H), 2.29-2.07 (m, 4H), 2.04-1.91 (m, 1H), 1.88-1.76 (m, 1H).

Example 167

5-{4-Cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 heating to 80° Celsius for 3 hours and using 2-chloro-4,6-dimethylpyrimidine. MS (ESI): mass calcd. for C₂₀H₂₀FN₅O, 365.17; m/z found, 366.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=1.1, 2H), 7.25-7.16 (m, 2H), 6.76 (s, 1H), 5.19 (s, 2H), 3.77-3.65 (m, 1H), 2.39 (s, 6H), 2.27-2.06 (m, 4H), 2.01-1.88 (m, 1H), 1.85-1.75 (m, 1H).

Example 168

4-(3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy)-6-isopropylpyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 164 heating the reaction for 18 hours and using 2-amino-4-chloro-6-isopropylpyrimidine. MS (ESI): mass calcd. for C₂₁H₂₃FN₆O, 394.19; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.04 (s, 1H), 7.76 (m, 1H), 7.20 (d, J=8.2 Hz, 1H), 6.12 (s, 1H), 5.03 (s, 2H), 4.75 (s, 2H), 3.60 (p, J=8.8, 1H), 2.85-2.71 (m, 1H), 2.30-2.06 (m, 4H), 2.05-1.90 (m, 1H), 1.89-1.74 (m, 1H), 1.24 (d, J=6.9, 6H).

Example 169

2-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide

The title compound was prepared using conditions similar to those described in Example 160 heating at 80° Celsius via microwave radiation for 2 hours and using 2-chloropyrimidine-4-carboxamide. MS (ESI): mass calcd. for C₁₉H₁₇FN₆O₂, 380.14; m/z found, 381.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (d, J=4.9, 1H), 8.44 (s, 2H), 8.21 (s, 1H), 7.98 (s, 1H), 7.77 (d, J=4.9, 1H), 7.52-7.42 (m, 1H), 7.30 (d, J=8.2, 1H), 6.89 (s, 2H), 3.63-3.51 (m, 1H), 2.15-2.00 (m, 4H), 1.99-1.84 (m, 1H), 1.81-1.68 (m, 1H).

Example 170

5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine Trifluoroacetate Salt

The title compound was prepared using conditions similar to those described in Example 164 heating the reaction at 140° Celsius for 18 hours and using 6-chloro-4-pyrimidinyl methyl ether. Both, (4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine trifluoroacetate salt and 6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol trifluoroacetate (Example 171), were isolated from this reaction. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂, 367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41-8.36 (d, J=1.2, 2H), 8.33-8.26 (s, 1H), 7.44-7.34 (m, 1H), 7.26-7.17 (d, J=8.1, 1H), 7.03-6.88 (s, 1H), 5.73-5.67 (s, 1H), 3.54-3.39 (m, 1H), 2.18-1.96 (m, 4H), 1.95-1.82 (m, 1H), 1.76-1.64 (m, 1H), 3.32-3.26 (m, 3H).

Example 171

6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol Trifluoroacetate Salt

Formed as an additional product in the formation of 5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine (Example 170). MS (ESI): mass calcd. for C₁₈H₁₆FN₅O₂, 353.13; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 8.42 (d, J=1.2, 2H), 8.07-8.01 (m, 1H), 7.42-7.34 (m, 1H), 7.20 (d, J=8.2, 1H), 7.18-6.94 (m, 2H), 5.62 (s, 1H), 3.54-3.39 (m, 1H), 2.19-1.96 (m, 4H), 1.96-1.81 (m, 1H), 1.77-1.64 (m, 1H).

Example 172

6-Amino-3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared using analogous conditions described in Intermediate A's Step D using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 2-amino-5-bromo-6-cyanopyrazine. MS (ESI): mass calcd. for C₁₆H₁₅FN₄O, 298.12; m/z found, 299.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.21 (s, 1H), 7.21-7.16 (m, 1H), 7.16-7.10 (m, 1H), 3.86-3.76 (m, 1H), 2.39-2.30 (m, 2H), 2.21-2.09 (m, 2H), 2.09-1.98 (m, 1H), 1.91-1.81 (m, 1H).

Example 173

6-Amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared using analogous conditions described in Intermediate B utilizing 6-amino-3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C₁₅H₁₃FN₄O, 284.11; m/z found, 285.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.17 (s, 1H), 7.13-7.07 (m, 1H), 6.95-6.90 (dd, J=8.0, 6.8, 1H), 3.89-3.79 (m, 1H), 2.43-2.33 (m, 2H), 2.25-2.14 (m, 2H), 2.13-2.01 (m, 1H), 1.92-1.83 (m, 1H).

Example 174

3-{[3-(5-Amino-3-cyanopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic Acid

The title compound was prepared using analogous conditions described in Example 1 using 6-amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile and methyl 3-(bromomethyl)benzoate. MS (ESI): mass calcd. for C₂₃H₁₉FN₄O₃, 418.14; m/z found, 419.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.22 (s, 1H), 8.09-8.05 (m, 1H), 7.96-7.91 (m, 1H), 7.73-7.68 (m, 1H), 7.57-7.52 (m, 1H), 7.36 (s, 2H), 7.33-7.26 (m, 2H), 5.09 (s, 2H), 3.80-3.70 (p, J=9.0, 1H), 2.26-2.15 (m, 2H), 2.15-2.04 (m, 2H), 1.99-1.88 (m, 1H), 1.84-1.73 (m, 1H).

Example 175

2-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using analogous conditions described in Intermediate A Step D using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 5-bromo-4,7-diazaindole. MS (ESI): mass calcd. for C₁₇H₁₆FN₃O, 297.13; m/z found, 298.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 9.43-9.28 (s, 1H), 8.72-8.67 (d, J=2.6, 1H), 7.67-7.58 (m, 2H), 7.19-7.13 (m, 1H), 6.82-6.78 (dd, J=3.7, 1.9, 1H), 3.96-3.89 (d, J=1.3, 3H), 3.89-3.77 (m, 1H), 2.42-2.32 (m, 2H), 2.21-2.11 (m, 2H), 2.10-1.99 (m, 1H), 1.92-1.83 (m, 1H).

Example 176

6-Cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol

The title compound was prepared using analogous conditions described in Intermediate B starting with 2-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): mass calcd. for C₁₆H₁₄FN₃O, 283.11; m/z found, 284.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 9.16 (s, 1H), 8.67 (d, J=2.6, 1H), 7.69-7.61 (m, 1H), 7.49-7.39 (m, 1H), 7.14 (d, J=8.1, 1H), 6.84-6.77 (m, 1H), 5.48 (s, 1H), 3.89-3.76 (m, 1H), 2.48-2.34 (m, 2H), 2.30-2.15 (m, 2H), 2.16-1.99 (m, 1H), 1.96-1.82 (m, 1H).

Example 177

2-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-5H-pyrrolo[2,3-b]pyrazine Trifluoroacetate Salt

To a 5 mL vial containing a stir bar, 6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol (40 mg, 0.14 mmol) and 4-(trifluoromethyl)benzyl bromide (41 mg, 0.17 mmol) were added KOH (24 mg, 0.42 mmol) and 0.78 mL of DMSO. The resultant mixture was stirred at rt for approximately 20 hours. The mixture was passed through a syringe filter and the filtrate subjected to HPLC purification affording the title compound (12 mg, 15%). MS (ESI): mass calcd. for C₂₄H₁₉F₄N₃O, 441.15; m/z found, 442.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.64 (d, J=2.0, 1H), 7.76 (dd, J=3.5, 2.7, 1H), 7.74-7.64 (m, 3H), 7.61 (d, J=8.1, 2H), 7.28-7.23 (m, 1H), 6.92 (dd, J=3.7, 1.9, 1H), 5.14 (s, 2H), 3.82 (p, J=8.7, 1H), 2.37-2.26 (m, 2H), 2.25-2.11 (m, 2H), 2.11-1.97 (m, 1H), 1.94-1.79 (m, 1H).

Example 178

2-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine Step A

2-(3-(Benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b] was prepared using procedures similar to those described in Example 216 utilizing 5-bromo-4,7-diazaindole. MS (ESI): mass calcd. for C₁₉H₁₃ClFN₃O, 353.07; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.70 (d, J=2.9, 1H), 7.72-7.65 (m, 2H), 7.58-7.51 (m, 2H), 7.44-7.30 (m, 4H), 6.82 (dd, J=3.7, 1.9, 1H), 5.20 (s, 2H).

Step B

The title compound was prepared using analogous conditions described in Example 83 using 2-(3-(benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): mass calcd. for C₂₃H₂₀FN₃O, 373.16; m/z found, 374.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.66 (s, 1H), 7.76-7.65 (m, 2H), 7.51-7.46 (m, 2H), 7.45-7.33 (m, 3H), 7.24 (d, J=8.3, 1H), 6.88 (m, 1H), 5.09 (s, 2H), 3.88-3.76 (m, 1H), 2.36-2.26 (m, 2H), 2.22-2.09 (m, 2H), 2.09-1.95 (m, 1H), 1.91-1.81 (m, 1H).

Example 179

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyridin-2-amine Hydrochloride Salt

Solid (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (350 mg, 1.56 mmol), 2-amino-5-bromopyridine (270 mg, 1.56 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (102 mg, 0.16 mmol) were placed in a round-bottomed flask under nitrogen. The flask was then charged with sparged THF (7 mL), KOH (760 mg, 14 mmol), and water (2 mL). The reaction mixture was stirred at room temperature overnight, then treated with EtOAc (20 mL). The mixture was dried, filtered, and concentrated to dryness. The residue was subjected to FCC to give pure title compound. The material was converted to a hydrochloride salt by dissolving in ether (10 mL) followed by adding a solution of 4 M HCl in 1,4-dioxane (0.3 mL). The precipitate was collected by filtration, washed with ether, and dried to yield the title compound (330 mg, 78%). MS (CI): mass calcd. for C₁₆H₁₇FN₂O, 272.13; m/z found, 273.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 14.12 (s, 1H), 8.31-8.05 (m, J=22.9, 5.6, 4H), 7.28-7.19 (m, 2H), 7.08 (d, J=9.3, 1H), 3.83 (d, J=0.8, 3H), 3.80-3.71 (m, 1H), 2.35-2.25 (m, 2H), 2.16-1.96 (m, 3H), 1.87-1.77 (m, J=18.5, 8.7, 1H).

Intermediate F

5-(4-Cyclobutyl-2-fluoro-3-hydroxyphenyl)pyridin-2-amine

A solution consisting of 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyridin-2-amine (333 mg, 1.08 mmol) and DCM (10 mL) was cooled to −78° Celsius, and then treated with 1 M BBr₃ in DCM (3.3 mL, 3.3 mmol) dropwise. The solution was maintained at −78° Celsius for 30 min, then warmed to room temperature and stirred overnight. The reaction mixture was poured into a beaker containing ice and saturated NaHCO₃, then extracted with EtOAc. The organic phase was isolated, dried and concentrated to dryness to afford the title compound. MS (CI): mass calcd. for C₁₅H₁₅FN₂O, 258.12; m/z found, 259.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.29 (d, J=2.0, 1H), 8.05 (s, 1H), 7.59-7.46 (m, 1H), 7.01 (d, J=8.0, 1H), 6.82 (m, 1H), 6.52 (dd, J=8.6, 0.6, 1H), 6.10 (s, 2H), 3.77-3.66 (m, J=8.6, 1H), 2.32-2.21 (m, 2H), 2.14-2.02 (m, 2H), 2.02-1.90 (m, 1H), 1.85-1.72 (m, 1H).

Example 180

5-Methyl-4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoate

A mixture of 5-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyridin-2-amine (50 mg, 0.19 mmol), Cs₂CO₃ (190 mg, 0.58 mmol), methyl 4-(bromomethyl)benzoate (56 mg, 0.25 mmol), and DMF (1 mL) was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with EtOAc. The organic phase was isolated, dried, concentrated to dryness and the residue subjected to FCC to give the title compound (74 mg, 94%). MS (CI): mass calcd. for C₂₄H₂₃FN₂O₃, 406.17; m/z found, 407.3 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.09 (s, 1H), 8.05-7.97 (m, 2H), 7.62 (d, J=8.4, 2H), 7.57 (d, J=8.6, 1H), 7.23-7.12 (m, 2H), 6.52 (dd, J=8.6, 0.6, 1H), 6.15 (s, 2H), 5.10 (s, 2H), 3.87 (s, 3H), 3.79-3.67 (m, J=8.8, 1H), 2.25-2.15 (m, 2H), 2.14-2.02 (m, 2H), 2.00-1.89 (m, 1H), 1.83-1.72 (m, J=8.9, 8.4, 1H).

Example 181

4-((3-(6-Aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoic acid

A mixture of 5-methyl-4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)-benzoate (54 mg, 0.13 mmol), KOH (2 M, 0.3 mL), THF (2 mL), and MeOH (1 mL) was stirred 16 hours at room temperature. The mixture was concentrated to dryness, treated with water (2 mL) and HCl (1M, 0.75 mL). The resulting precipitate was collected, washed with water, and dried to yield the title compound (0.48 mg, 92%). MS (CI): mass calcd. for C₂₃H₂₁FN₂O₃, 392.15; m/z found, 393.3 [M+H]⁺.

Intermediate F′

5-Bromo-1H-imidazo-[4,5-b]pyrazine

To a 50 mL round bottom flask fitted with a reflux condenser, under nitrogen were added 5-bromopyrazine-2,3-diamine (400 mg, 2.1 mmol) and triethyl orthoformate (3.1 g, 21.2 mmol). The mixture was heated to reflux and stirred for 24 h. The reaction was cooled to rt, concentrated to dryness and the residue purified by HPLC to give 320 mg (76% yield) of the title compound. MS (ESI): mass calcd. for C₅H₃BrN₄, 197.95; m/z found, 199.1 [M+H]⁺.

Example 182

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyrazine

To a mixture of 5-bromo-1H-imidazo-[4,5-b]pyrazine (50 mg, 0.25 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (67 mg, 0.30 mmol) and [1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II)CH₂Cl₂ (10 mg, 0.01 mmol) in a microwave vial were added acetonitrile (2.0 mL) and sodium bicarbonate solution (saturated 2.0 mL). The reaction was de-gassed with nitrogen, vial capped and irradiated via microwave radiation for 90 min at 110° Celsius before cooling to rt. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL) and brine (25 mL). dried (Na₂SO₄) and concentrated to dryness. The crude residue was purified by HPLC yielding the title compound (30 mg, 40%). MS (ESI): mass calcd. for C₁₆H₁₅FN₄O, 298.12; m/z found, 299.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due to the presence of multiple conformations on the NMR time-scale, peaks listed for identification purposes only: δ 11.38 (s), 10.85 (s), 9.02 (d, J=2.03), 8.91 (d, J=2.10), 8.53 (s), 7.87-7.77 (m), 7.58-7.49 (m), 7.26-7.17 (m), 3.96 (s), 3.94 (s), 3.92-3.80 (m), 2.51-2.32 (m), 2.30-1.98 (m), 1.97-1.78 (m).

Example 183

6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine

The title compound was prepared using methods analogous to those described in Example 182 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 6-bromo-3H-imidazo[4,5-b]pyridine. MS (ESI): mass calcd. for C₁₇H₁₆FN₃O, 297.13; m/z found, 298.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.41 (s, 1H), 8.62 (s, 1H), 8.30 (s, 2H), 7.22-7.12 (m, 2H), 3.94 (s, 3H), 3.92-3.78 (m, 1H), 2.48-2.33 (m, 2H), 2.29-2.00 (m, 3H), 1.97-1.79 (m, 1H).

Example 184

7-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in a manner similar to that described in Example 1 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₂, 314.14; m/z found, 315.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.86 (s, 1H), 7.19 (s, 1H), 7.09-7.02 (m, 2H), 5.44 (s, 1H), 4.28-4.19 (m, 2H), 3.89 (s, 3H), 3.84-3.75 (m, 1H), 3.59 (s, 2H), 2.39-2.31 (m, 2H), 2.20-2.10 (m, 2H), 2.09-2.00 (m, 1H), 1.90-1.82 (m, 1H).

Example 185

6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol

A solution of 7-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (0.103 g, 0.328 mmol) in CH₂Cl₂ (10 mL) was cooled to −78° Celsius and treated drop wise with BBr₃ (1 M in CH₂Cl₂, 1.6 mL). The reaction mixture was stirred for 16 hours with gradual warming to room temperature. The mixture was concentrated to dryness, and the residue purified by HPLC to give title compound (81 mg, 82%). MS (ESI): mass calcd. for C₁₇H₁₇FN₂O₂, 300.13; m/z found, 301.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (m, 1H), 7.20 (m, 1H), 7.02 (d, J=8.1, 1H), 6.83 (m, 1H), 4.27-4.23 (m, 2H), 3.88-3.74 (m, 1H), 3.63-3.52 (m, 2H), 2.42-2.32 (m, 2H), 2.23-2.10 (m, 2H), 2.08-2.00 (m, 1H), 1.92-1.80 (m, 1H).

Example 186

7-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and (bromomethyl)benzene. MS (ESI): mass calcd. for C₂₄H₂₃FN₂O₂, 390.17; m/z found, 391.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.72 (s, 1H), 7.64-7.61 (m, 1H), 7.47-7.42 (m, 2H), 7.41-7.31 (m, 3H), 7.23-7.16 (m, 2H), 5.05 (s, 2H), 4.36 (t, J=4.6, 2H), 3.81-3.73 (m, 1H), 3.73-3.65 (m, 2H), 2.31-2.20 (m, 2H), 2.17-1.95 (m, 3H), 1.87-1.79 (m, 1H).

Example 187

3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 3-(bromomethyl)benzonitrile. MS (ESI): mass calcd. for C₂₅H₂₂FN₃O₂, 415.17; m/z found, 416.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.82 (s, 1H), 7.78 (d, J=7.8, 1H), 7.74-7.70 (m, 2H), 7.68-7.64 (m, 1H), 7.59 (m, 1H), 7.27-7.20 (m, 2H), 5.12 (s, 2H), 4.40-4.33 (m, 2H), 3.84-3.68 (m, 3H), 2.34-2.24 (m, 2H), 2.20-1.97 (m, 3H), 1.90-1.81 (m, 1H).

Example 188

7-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 1-(bromomethyl)-3-(methylsulfonyl)benzene. MS (ESI): mass calcd. for C₂₅H₂₅FN₂O₄S, 468.15; m/z found, 469.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.06 (s, 1H), 7.94 (d, J=7.9, 1H), 7.81 (d, J=7.7, 1H), 7.72 (s, 1H), 7.70-7.61 (m, 2H), 7.25-7.19 (m, 2H), 5.18 (s, 2H), 4.38-4.33 (m, 2H), 3.84-3.73 (m, 1H), 3.72-3.67 (m, 2H), 3.12 (s, 3H), 2.34-2.23 (m, 2H), 2.18-1.98 (m, 3H), 1.89-1.79 (m, 1H).

Example 189

7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 1-(bromomethyl)-4-(methylsulfonyl)benzene. MS (ESI): mass calcd. for C₂₅H₂₅FN₂O₄S, 468.15; m/z found, 469.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.02-7.96 (m, 2H), 7.74 (d, J=8.4, 3H), 7.65-7.62 (m, 1H), 7.27-7.20 (m, 2H), 5.17 (s, 2H), 4.38-4.34 (m, 2H), 3.87-3.74 (m, 1H), 3.73-3.66 (m, 2H), 3.13 (d, J=3.7, 3H), 2.34-2.24 (m, 2H), 2.21-1.98 (m, 3H), 1.90-1.80 (m, 1H).

Example 190

4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 4-(bromomethyl)benzonitrile. MS (ESI): mass calcd. for C₂₅H₂₂FN₃O₂, 415.17; m/z found, 416.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.80-7.75 (m, 2H), 7.72 (d, J=0.8, 1H), 7.69-7.61 (m, 3H), 7.26-7.19 (m, 2H), 5.13 (s, 2H), 4.39-4.31 (m, 2H), 3.86-3.74 (m, 1H), 3.72-3.68 (m, 2H), 2.34-2.23 (m, 2H), 2.21-1.95 (m, 3H), 1.90-1.80 (m, 1H).

Example 191

7-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 1-(bromomethyl)-4-(trifluoromethyl)benzene. MS (ESI): mass calcd. for C₂₅H₂₂F₄N₂O₂, 458.16; m/z found, 459.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.74-7.61 (m, 6H), 7.26-7.19 (m, 2H), 5.14 (s, 2H), 4.39-4.31 (m, 2H), 3.87-3.74 (m, 1H), 3.72-3.68 (m, 2H), 2.33-2.22 (m, 2H), 2.19-1.97 (m, 3H), 1.89-1.80 (m, 1H).

Example 192

3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 3-(bromomethyl)benzamide. MS (ESI): mass calcd. for C₂₅H₂₄FN₃O₃, 433.18; m/z found, 434.2 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.01-7.97 (m, 1H), 7.88-7.83 (m, 1H), 7.74-7.71 (m, 1H), 7.67-7.60 (m, 2H), 7.53-7.47 (m, 1H), 7.23-7.19 (m, 2H), 5.14-5.10 (m, 2H), 4.38-4.33 (m, 2H), 3.83-3.75 (m, 1H), 3.72-3.67 (m, 2H), 2.32-2.22 (m, 2H), 2.17-2.07 (m, 2H), 2.06-1.96 (m, 1H), 1.88-1.80 (m, 1H).

Example 193

4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 4-(bromomethyl)benzamide. MS (ESI): mass calcd. for C₂₅H₂₄FN₃O₃, 433.18; m/z found, 434.3 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 7.90 (d, J=8.3, 2H), 7.72 (s, 1H), 7.62 (d, J=5.3, 1H), 7.56 (d, J=8.3, 2H), 7.23-7.20 (m, 2H), 5.12 (s, 2H), 4.37-4.34 (m, 2H), 3.82-3.76 (m, 1H), 3.72-3.69 (m, 2H), 2.31-2.24 (m, 2H), 2.17-2.11 (m, 2H), 2.06-1.99 (m, 1H), 1.88-1.81 (m, 1H).

Example 194

7-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described in Example 28 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 2-bromo-6-(trifluoromethyl)pyridine. MS (ESI): mass calcd. for C₂₃H₁₉F₄N₃O₂, 445.14; m/z found, 446.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.05 (m, 1H), 7.71 (d, J=1.4, 1H), 7.62-7.59 (m, 1H), 7.51 (d, J=7.4, 1H), 7.42 (m, 1H), 7.36-7.30 (m, 2H), 4.37-4.33 (m, 2H), 3.72-3.68 (m, 2H), 3.67-3.61 (m, 1H), 2.22-2.09 (m, 4H), 2.03-1.92 (m, 1H), 1.85-1.76 (m, 1H).

Example 195

(4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic Acid

A solution of 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol (50 mg, 0.17 mmol) and 2-(4-(bromomethyl)phenyl)acetic acid (38 mg, 0.17 mmol) in DMSO (1 mL) was treated with potassium tert-butoxide (38 mg, 0.33 mmol) and stirred for 16 hours at 80° Celsius. The reaction was then cooled to rt, filtered, and the filtrate subjected directly to HPLC purification to give (4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic acid (8 mg, 9%). MS (ESI): mass calcd. for C₂₆H₂₅FN₂O₄, 448.18; m/z found, 449.2 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 7.72 (s, 1H), 7.60 (s, 1H), 7.40 (d, J=8.1, 2H), 7.31 (d, J=8.1, 2H), 7.19 (d, J=6.0, 2H), 5.04 (s, 2H), 4.38-4.32 (m, 2H), 3.78-3.72 (m, 1H), 3.71-3.67 (m, 2H), 3.63 (s, 2H), 2.29-2.22 (m, 2H), 2.16-2.07 (m, 2H), 2.04-1.97 (m, 1H), 1.84 (t, J=9.6, 1H).

Example 196

4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzoic Acid

Prepared in a manner similar to that described in Example 195 by reaction of 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol 4-(bromomethyl)benzoic acid. MS (ESI): mass calcd. for C₂₅H₂₃FN₂O₄, 434.16; m/z found, 435.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.07-8.03 (m, 2H), 7.73 (d, J=1.3, 1H), 7.66-7.64 (m, 1H), 7.57 (d, J=8.4, 2H), 7.22 (d, J=4.4, 2H), 5.13 (s, 2H), 4.368-4.35 (m, 2H), 3.83-3.76 (m, 1H), 3.74-3.69 (m, 2H), 2.31-2.25 (m, 2H), 2.17-2.09 (m, 2H), 2.06-1.98 (m, 1H), 1.88-1.81 (m, 1H).

Example 197

3-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine

The title compound was prepared in a manner similar to that described in Example 1 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 3-chloro-7H-pyrrolo[2,3-c]pyridazine. MS (ESI): mass calcd. for C₁₇H₁₆FN₃O, 297.13; m/z found, 298.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 12.05 (s, 1H), 8.15 (d, J=2.2, 1H), 7.80 (d, J=3.4, 1H), 7.71 (m, 1H), 7.21 (d, J=8.1, 1H), 6.61 (d, J=3.4, 1H), 3.94 (d, J=1.2, 3H), 2.44-2.35 (m, 2H), 2.25-2.14 (m, 2H), 2.13-2.05 (m, 1H), 1.81 (d, J=7.1, 2H).

Example 198

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

A reaction flask containing 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (0.5 g, 2.5 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (0.563 g, 2.51 mmol), potassium carbonate (1.041 g, 7.54 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)CH₂Cl₂ (0.093 g, 0.13 mmol) was sealed and the atmosphere exchanged with N₂ (3×). The flask was charged with freshly sparged DMF (2 mL), toluene (5 mL), and deionized H₂O (5 mL). The mixture was heated for 16 hours at 80° Celsius. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with brine (3×50 mL). The organic layer was isolated, dried over MgSO₄, filtered, and concentrated to dryness. The residue was purified by FCC to give the title compound (0.605 g, 81%). MS (ESI): mass calcd. for C₁₈H₁₉FN₂O, 298.15; m/z found, 299.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=0.9 Hz, 1H), 7.44 (s, 1H), 7.09-7.01 (m, 2H), 4.62 (s, 1H), 3.89 (d, J=1.3 Hz, 3H), 3.85-3.74 (m, 1H), 3.72-3.63 (m, 2H), 3.12 (t, J=8.4 Hz, 2H), 2.41-2.30 (m, 2H), 2.22-1.99 (m, 3H), 1.95-1.81 (m, 1H).

Example 199

6-Cyclobutyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol

Prepared in a manner similar to that described in Example 185 by reaction of 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. MS (ESI): mass calcd. for C₁₇H₁₇FN₂O, 284.13; m/z found, 285.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.82-7.76 (m, 1H), 7.64 (s, 1H), 7.06 (d, J=8.0, 1H), 6.86 (m, 1H), 3.95 (t, J=8.3, 2H), 3.85-3.72 (m, 1H), 3.30-3.22 (m, 2H), 2.41-2.29 (m, 2H), 2.21-1.99 (m, 3H), 1.90-1.81 (m, 1H).

Intermediate G

3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenol Step A

To a 100 mL round-bottomed flask were added a stir bar, 2-(1,1-dimethylethyl)-6-fluorophenol (2.62 g, 15.6 mmol), tert-butyldimethylchlorosilane (4.84 g, 31.1 mmol), imidazole (1.46 g, 21.5 mmol) and dry DMF (48 mL). The flask was purged with nitrogen and heated at 60° Celsius for 24 hours. The mixture was cooled to room temperature and then partitioned between EtOAc and water. The EtOAc layer was washed with water followed by brine. The organic layer was dried over Na₂SO₄ and concentrated. Purification by FCC yielded tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (4.2 g, 96%). ¹H NMR (600 MHz, CDCl₃) δ 7.04 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 1.56 (s, 6H), 1.39 (s, 9H), 1.01 (d, J=0.7, 9H).

Step B

To a 100 mL round-bottomed flask were added a stir bar, dry THF (15.0 mL) and 2,2,6,6-tetramethylpiperidine (2.3 mL, 13.6 mmol). The flask was cooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (5.46 mL, 13.6 mmol) over 2 min. The resultant mixture was stirred for 5 min and then warmed to 0° Celsius. After 65 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)₃ (17.5 mL, 13.6 mmol) over 4 min. After 20 min, a solution consisting of tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (2.57 g, 9.1 mmol) and dry THF (5.0 mL) was added over the course of 2 min and stirring continued for 3 hours. The reaction was gradually warmed to room temperature while stirring for 18 hours, after which time, HOAc (5.2 mL, 91 mmol) was added. The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL), the extract dried over Na₂SO₄, filtered and concentrated to dryness. Purification by FCC yielded (4-(tert-butyl)-3-((tert-butyldimethylsilyl)oxy)-2-fluorophenyl)boronic acid (2.13 g, 72%).

Step C

(4-(tert-Butyl)-3-((tert-butyldimethylsilyl)oxy)-2-fluorophenyl)boronic acid was coupled to 2-amino-5-bromopyrazine in an analogous manner to Step D in Intermediate A to give the title compound (658 mg, 78%). MS (ESI): mass calcd. for C₁₄H₁₆FN₃O, 261.13; m/z found, 262.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (d, J=3.2, 1H), 8.21 (dd, J=2.3, 1.5, 1H), 7.93 (d, J=1.5, 1H), 7.11 (m, 1H), 6.98 (d, J=8.4, 1H), 6.56 (s, 2H), 1.32 (s, 9H).

Example 200

5-(4-tert-Butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrazin-2-amine

The title compound was formed as an additional product in the synthesis of Intermediate E in Step C (56 mg 5%) yield. MS (ESI): mass calcd. for C₂₀H₃₀FN₃OSi, 375.21; m/z found, 376.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.40 (m, 1H), 8.09 (d, J=1.4, 1H), 7.35-7.28 (m, 1H), 7.13 (dd, J=8.5, 1.5, 1H), 4.62 (s, 2H), 1.41 (s, 9H), 1.02 (d, J=0.7, 9H), 0.34 (d, J=4.3, 6H).

Example 201

5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 heating for 4 hours at 120° Celsius and using Intermediate G. MS (ESI): mass calcd. for C₁₈H₁₈FN₅O, 339.15; m/z found, 340.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (d, J=4.8, 2H), 8.22 (s, 1H), 8.00 (d, J=1.4, 1H), 7.71-7.62 (m, 1H), 7.35-7.26 (m, 2H), 6.68 (s, 2H), 1.30 (s, 9H).

Example 202

6-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to those described in Example 164 heating for 5 hours at 120° Celsius using Intermediate G and 4-amino-6-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₉FN₆O, 354.16; m/z found, 355.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.08-7.99 (m, 2H), 7.65 (m, 1H), 7.29 (d, J=8.6, 1H), 6.92 (s, 2H), 6.71 (s, 2H), 5.94 (s, 1H), 1.30 (s, 9H).

Example 203

2-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to those described in Example 164 heating for 15 hours at 140° Celsius using Intermediate G and 4-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₉FN₆O, 354.16; m/z found, 355.0 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.25 (s, 1H), 8.04 (d, J=1.4, 1H), 7.88 (d, J=5.9, 1H), 7.66-7.59 (m, 1H), 7.30 (dd, J=8.6, 1.2, 1H), 6.24 (d, J=5.9, 1H), 1.37 (s, 9H).

Example 204

5-{4-tert-Butyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 164 heating for 3 hours at 120° Celsius using Intermediate G and 6-chloro-4-pyrimidinyl methyl ether giving title compound and Example 205. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O₂, 369.16; m/z found, 370.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.42 (m, 1H), 8.08 (d, J=1.5, 1H), 7.98 (s, 1H), 7.78-7.69 (m, 1H), 7.32-7.27 (m, 1H), 5.90 (s, 1H), 4.67 (s, 2H), 3.51 (s, 3H), 1.37 (s, 9H).

Example 205

5-(4-tert-Butyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

Title compound was formed as an additional product from the preparation of Example 204. MS (ESI): mass calcd. for C₁₅H₁₈FN₃O, 275.14; m/z found, 276.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50-8.45 (m, 1H), 8.09 (d, J=1.5, 1H), 7.48-7.40 (m, 1H), 7.17-7.09 (m, 1H), 4.64 (s, 2H), 3.99 (d, J=2.2, 3H), 1.40 (s, 9H).

Intermediate H

3-(2-Aminopyrimidin-5-yl)-6-tert-butyl-2-fluorophenol

The title compound was prepared using conditions similar to those described Intermediate E using 2-amino-5-bromopyrimidine in Step C. MS (ESI): mass calcd. for C₁₄H₁₆FN₃O, 261.13; m/z found, 262.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 8.39 (d, J=1.5, 2H), 7.02 (dd, J=8.3, 1.3, 1H), 6.89-6.76 (m, 3H), 1.37 (s, 9H).

Example 206

5-(4-tert-Butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrimidin-2-amine

Formed as an additional product during formation of Intermediate F in Step C. MS (ESI): mass calcd. for C₂₀H₃₀FN₃OSi, 375.21; m/z found, 376.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.53-8.40 (m, 2H), 7.15-7.08 (m, 1H), 6.87-6.77 (m, 1H), 5.22 (s, 2H), 1.41 (s, 9H), 1.01 (s, 9H), 0.33 (d, J=4.2, 6H).

Example 207

5-[4-tert-Butyl-2-fluoro-3-(pyridin-2-yloxy)phenyl]pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 heating at 120° Celsius for 2 hours and using Intermediate H. MS (ESI): mass calcd. for C₁₈H₁₈FN₅O, 339.15; m/z found, 340.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (d, J=4.8, 2H), 8.41 (d, J=1.4, 2H), 7.43-7.35 (m, 1H), 7.35-7.25 (m, 2H), 6.88 (s, 2H), 1.30 (s, 9H).

Example 208

5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 164 heating for 15 hours at 140° Celsius using Intermediate H and 4-amino-6-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₉FN₆O, 354.16; m/z found, 355.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=1.0, 2H), 8.04 (s, 1H), 7.41-7.32 (m, 1H), 7.27 (d, J=8.4, 1H), 6.89 (d, J=4.5, 4H), 5.97-5.89 (m, 1H), 1.30 (s, 9H).

Example 209

5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to those described in Example 164 heating for 13 hours at 140° Celsius using Intermediate H and 4-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₉FN₆O, 354.16; m/z found, 355.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=1.2, 2H), 8.02 (d, J=5.7, 1H), 7.29-7.24 (m, 1H), 7.18-7.09 (m, 1H), 6.12 (d, J=5.7, 1H), 4.98 (s, 2H), 4.80 (s, 2H), 1.40 (s, 9H).

Example 210

5-(4-Bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine Step A: (4-Bromo-2-fluoro-3-methoxyphenyl)boronic Acid

A solution of 2,2,6,6-tetramethylpiperidine TMP (0.98 ml, 5.76 mmol) in THF (9.8 ml) was cooled to −78° Celsius under N₂. To the solution was then added n-BuLi (2.21 N in hexanes, 2.45 mL, 5.41 mmol) slowly over the course of a couple of min. The mixture was then warmed to 0° Celsius for 20-30 min and treated with triisopropyl borate (1.25 ml, 5.41 mmol) was added. After 5 min, 1-bromo-3-fluoro-2-methoxybenzene (1.0 g, 4.9 mmol) was slowly added and the reaction was stirred at −78° Celsius. After 1.5 hours, the resulting mixture was warmed to room temperature with AcOH (2.8 ml, 49 mmol), poured into water, and extracted with EtOAc. The organic extract was isolated, dried over MgSO₄, filtered and concentrated to dryness to yield (5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-yl)boronic acid as a solid (940 mg, 77%) that was used without further purification.

Step B

A mixture of the crude (4-bromo-2-fluoro-3-methoxyphenyl)boronic acid (940 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (1.31 g, 7.56 mmol) was treated with EtOH (12.4 ml) and toluene (12.8 ml) The resulting suspension was then treated with aqueous Na₂CO₃ (2.0 N, 9.44 ml, 18.9 mmol). The resulting mixture was then sparged with nitrogen for 10 min, before adding Pd(PPh₃)₄ (218 mg, 0.189 mmol) and heating at 80° Celsius for 17 hours. The reaction was cooled to room temperature and partitioned between saturated NH₄Cl and EtOAc. The organic layer was dried over MgSO₄ and concentrated to dryness. The residue was suspended in DCM was and the resultant solid isolated by filtration to afford the title compound (300 mg, 27%), which was used without further purification. Additional product was obtained by concentrating the DCM layer and subjecting the residue to FCC to afford the title compound (560 mg, 50%). MS (ESI): mass calcd. for C₁₁H₉BrFN₃O, 296.99; m/z found, 298.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (dd, J=2.6, 1.5, 1H), 8.00 (d, J=1.5, 1H), 7.54-7.49 (m, 2H), 6.78 (s, 2H), 3.90 (d, J=0.6, 3H).

Example 211

5-(4-Cyclopentyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

A microwave vial was charged with 5-(4-bromo-2-fluoro-3-methoxyphenyl)-pyrazin-2-amine (50 mg, 0.17 mmol), palladium acetate (2.9 mg, 0.013 mmol) and 2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl (7.7 mg, 0.018 mmol). The vial was evacuated and back filled with nitrogen. Cyclopentylzinc bromide (0.5 M in THF, 0.67 ml, 0.34 mmol) was then added and the mixture heated at 70° Celsius for 19 hours. The reaction was cooled to rt and the mixture subjected to HPLC purification to afford the title compound (7 mg, 15%). MS (ESI): mass calcd. for C₁₆H₁₈FN₃O, 287.14; m/z found, 288.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.50-8.46 (m, 1H), 8.09 (d, J=1.5, 1H), 7.54-7.48 (m, 1H), 7.09 (dd, J=8.3, 1.1, 1H), 4.65 (s, 2H), 3.94 (d, J=1.2, 3H), 3.42-3.33 (m, 1H), 2.11-1.99 (m, 2H), 1.88-1.78 (m, 2H), 1.77-1.66 (m, 2H), 1.59-1.53 (m, 2H).

Example 212

5-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 83 using cyclopentylzinc bromide (0.5 M solution in THF). MS (ESI): mass calcd. for C₂₂H₂₂FN₃O, 363.17; m/z found, 364.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 8.10 (s, 1H), 7.58-7.51 (m, 1H), 7.51-7.45 (m, 2H), 7.43-7.32 (m, 3H), 7.10 (dd, J=8.3, 1.1, 1H), 5.09 (s, 2H), 4.66 (s, 2H), 3.43-3.31 (m, 1H), 2.00-1.89 (m, 2H), 1.84-1.72 (m, 2H), 1.71-1.47 (m, 4H).

Example 213

5-[4-Cyclopentyl-2-fluoro-3-(1-methylethoxy)phenyl]pyrazin-2-amine Step A

5-(4-Chloro-2-fluoro-3-isopropoxyphenyl)pyrazin-2-amine was prepared using procedures similar to those described in Example 216 utilizing 4-chloro-2-fluoro-3-isopropoxyphenylboronic acid. MS (ESI): mass calcd. for C₁₃H₁₃ClFN₃O, 281.07; m/z found, 282.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=3.6, 2H), 7.60 (m, 1H), 7.31-7.22 (m, 1H), 4.52 (m, 1H), 1.41-1.38 (m, 6H).

Step B

The title compound was prepared using analogous conditions described in Example 83 using 5-(4-chloro-3-isopropoxyphenyl)pyrazin-2-amine and cyclopentylzinc bromide (0.5 M solution in THF). MS (ESI): mass calcd. for C₁₈H₂₂FN₃O, 315.17; m/z found, 316.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.48-8.45 (m, 1H), 8.08 (d, J=1.5, 1H), 7.52-7.46 (m, 1H), 7.10 (dd, J=8.3, 1.2, 1H), 4.64 (s, 2H), 4.48-4.38 (m, 1H), 3.49-3.40 (m, 1H), 2.10-2.01 (m, 2H), 1.88-1.79 (m, 2H), 1.75-1.67 (m, 2H), 1.58-1.48 (m, 3H), 1.35 (dd, J=6.1, 0.6, 6H).

Example 214

2-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine Step A

2-(3-(Benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine] was prepared using procedures similar to those described in Example 216 utilizing 5-bromo-4,7-diazaindole. MS (ESI): mass calcd. for C₁₉H₁₃ClFN₃O, 353.07; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.70 (d, J=2.9, 1H), 7.72-7.65 (m, 2H), 7.58-7.51 (m, 2H), 7.44-7.30 (m, 4H), 6.82 (dd, J=3.7, 1.9, 1H), 5.20 (s, 2H).

Step B

The title compound was prepared using analogous conditions described in Example 83 using 2-(3-(benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine and cyclopentylzinc bromide (0.5 M solution in THF). MS (ESI): mass calcd. for C₂₄H₂₂FN₃O, 387.1747; m/z found, 388.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.73 (d, J=2.8, 1H), 7.69-7.61 (m, 2H), 7.50 (dd, J=8.1, 6.5, 2H), 7.43-7.32 (m, 3H), 7.16 (dd, J=8.3, 1.1, 1H), 6.82 (dd, J=3.7, 1.9, 1H), 5.12 (s, 2H), 3.46-3.33 (m, 1H), 2.04-1.91 (m, 2H), 1.87-1.75 (m, 2H), 1.73-1.49 (m, 4H).

Example 215

5-[3-(Benzyloxy)-4-tert-butylphenyl]pyrazin-2-amine Step A: 2-(Benzyloxy)-4-bromo-1-(tert-butyl)benzene

5-Bromo-2-tert-butylphenol (1.08 g, 4.71 mmol), benzyl bromide (0.69 mL, 5.7 mmol) and Cs₂CO₃ (2.3 g, 7.1 mmol) were added to 23.6 mL of acetonitrile and stirred at room temperature for 64 hours. The reaction mixture was filtered and concentrated to dryness. Purification by FCC resulted in title compound (1.39 g, 92%).

Step B: 2-(3-(Benzyloxy)-4-(tert-butyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

2-(Benzyloxy)-4-bromo-1-(tert-butyl)benzene (495 mg, 1.55 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (482 mg, 1.86 mmol) were dissolved in 1,4-dioxane (10.3 mL) and treated with KOAc (461 mg, 4.65 mmol). The solution was sparged with N₂ and tris((E,E)-dibenzylideneacetone)dipalladium (42 mg, 0.047 mmol) and tricyclohexylphosphine (30 mg, 0.11 mmol) were added. The mixture was heated at 100° Celsius for 4 hours. The reaction mixture was filtered through anhydrous NaSO₄ and a plug of diatomacious earth, then subjected to FCC to give title compound (138 mg, 24%).

Step C

2-Amino-5-bromopyrazine (65 mg, 0.38 mmol) and 2-(3-(benzyloxy)-4-(tert-butyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, (138 mg, 0.38 mmol) were partially dissolved in DME (2.5 mL) and treated with of 2.0 M aqueous K₂CO₃ (0.83 mL). The solution was sparged and treated with Pd(dppf)Cl₂.CH₂Cl₂ (30 mg, 0.038 mmol). The mixture was stirred at room temperature for 64 hours. The mixture was dried, filtered through a pad of diatomacious earth and then subjected to FCC followed by HPLC to give the title compound (4 mg, 2%). MS (ESI): mass calcd. for C₂₁H₂₃N₃O, 333.18; m/z found, 334.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J=1.4, 1H), 8.18 (d, J=1.4, 1H), 7.56-7.48 (m, 3H), 7.45-7.32 (m, 6H), 5.21 (s, 2H), 1.42 (s, 10 OH).

Example 216

5-[3-(Benzyloxy)-4-chloro-2-fluorophenyl]pyrazin-2-amine

2-Amino-5-bromopyrazine (100 mg, 0.57 mmol) and 3-benzyloxy-4-chloro-2-fluorophenylboronic acid, (193 mg, 0.57 mmol) were partially dissolved in DME (2.5 mL) and treated with 2.0 M aqueous K₂CO₃ (0.83 mL). The solution was sparged and treated with Pd(dppf)Cl₂.CH₂Cl₂ (47 mg, 0.057 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was dried, filtered through a pad of diatomacious earth and then subjected to FCC to give the title compound (146 mg, 77%). MS (ESI): mass calcd. for C₁₇H₁₃ClFN₃O, 329.07; m/z found, 330.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd, J=2.4, 1.6, 1H), 8.06 (d, J=1.5, 1H), 7.61-7.50 (m, 3H), 7.43-7.31 (m, 3H), 7.24 (dd, J=8.9, 1.9, 1H), 5.16 (s, 2H), 4.78 (s, 2H).

Example 217

5-[3-(Benzyloxy)-4-cyclobutylphenyl]pyrazin-2-amine Step A

5-(3-Benzyloxy)-4-chlorophenyl)pyrazin-2-amine was prepared using procedures similar to those described in Example 216 utilizing (3-(benzyloxy)-4-chlorophenyl)-boronic acid. MS (ESI): mass calcd. for C₁₇H₁₄ClN₃O, 311.08; m/z found, 312.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (d, J=1.4, 1H), 8.03 (d, J=1.5, 1H), 7.59 (d, J=1.9, 1H), 7.55-7.48 (m, 2H), 7.47-7.36 (m, 4H), 7.33 (t, J=7.4, 1H), 5.24 (s, 2H), 4.69 (s, 2H).

Step B

The title compound was prepared using analogous conditions described in Example 83 using 5-(3-(benzyloxy)-4-chlorophenyl)pyrazin-2-amine. MS (ESI): mass calcd. for C₂₁H₂₁N₃O, 331.17; m/z found, 332.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=1.5, 1H), 8.06 (d, J=1.5, 1H), 7.50-7.45 (m, 3H), 7.45-7.37 (m, 3H), 7.36-7.28 (m, 2H), 5.15 (s, 2H), 4.60 (s, 2H), 3.88-3.78 (m, 1H), 2.41-2.30 (m, 2H), 2.23-2.10 (m, 2H), 2.09-1.95 (m, 1H), 1.88-1.78 (m, 1H).

Example 218

3-amino-6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared in a manner similar to that described in Example 198 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 3-amino-6-bromopyrazine-2-carbonitrile. MS (ESI): mass calcd. for C₁₆H₁₅FN₄O₂, 298.12; m/z found, 299.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.62-8.61 (m, 1H), 7.54-7.46 (m, 1H), 7.21-7.15 (m, 1H), 3.89-3.88 (m, 3H), 3.86-3.79 (m, 1H), 2.41-2.32 (m, 2H), 2.24-2.04 (m, 3H), 1.94-1.85 (m, 1H).

Example 219

6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described in Example 198 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 6-chloropyridazin-3-amine. MS (ESI): mass calcd. for C₁₅H₁₆FN₃O, 273.13; m/z found, 274.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.73-7.62 (m, 2H), 7.17-7.14 (m, 1H), 6.84-6.78 (m, 1H), 3.92-3.87 (m, 3H), 3.86-3.77 (m, 1H), 2.42-2.32 (m, 2H), 2.23-1.98 (m, 3H), 1.93-1.83 (m, 1H).

Example 220

6-Cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The title compound was prepared in a manner similar to that described in Example 185 by reaction of Intermediate I. MS (ESI): mass calcd. for C₁₇H₁₅FN₂O, 282.12; m/z found, 283.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.90-8.83 (m, 1H), 8.63-8.56 (m, 1H), 7.82-7.75 (m, 1H), 7.18-7.12 (m, 1H), 7.08-7.01 (m, 1H), 6.98-6.93 (m, 1H), 3.91-3.76 (m, 1H), 2.45-2.34 (m, 2H), 2.25-2.14 (m, 2H), 2.11-2.02 (m, 1H), 1.95-1.85 (m, 1H).

Example 221

6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol

The title compound was prepared in a manner similar to that described in Example 185 by reaction of 3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine. MS (ESI): mass calcd. for C₁₆H₁₄FN₃O, 283.11; m/z found, 284.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.69-8.65 (m, 1H), 8.57-8.51 (m, 1H), 7.31-7.27 (m, 1H), 7.21-7.16 (m, 1H), 7.10-7.05 (m, 1H), 3.95-3.82 (m, 1H), 2.46-2.38 (m, 2H), 2.26-2.07 (m, 3H), 1.95-1.86 (m, 1H).

Example 222

3-Amino-6-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared in a manner similar to that described in Example 185 by reaction of 3-amino-6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C₁₅H₁₃FN₄O, 284.11; m/z found, 285.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.63-8.58 (m, 1H), 7.27-7.20 (m, 1H), 7.11-7.05 (m, 1H), 3.89-3.74 (m, 1H), 2.42-2.31 (m, 2H), 2.24-1.99 (m, 3H), 1.92-1.81 (m, 1H).

Example 223

3-(6-Aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol

The title compound was prepared in a manner similar to that described in Example 185 by reaction of 6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyridazin-3-amine. MS (ESI): mass calcd. for C₁₄H₁₄FN₃O, 259.11; m/z found, 260.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.15-8.08 (m, 1H), 7.57-7.50 (m, 1H), 7.22-7.16 (m, 1H), 7.15-7.10 (m, 1H), 3.89-3.76 (m, 1H), 2.42-2.33 (m, 2H), 2.22-2.00 (m, 3H), 1.92-1.82 (m, 1H).

Example 224

5,5′-((Pyrimidine-2,4-diylbis(oxy))bis(4-cyclobutyl-2-fluoro-3,1-phenylene))bis(pyrazin-2-amine)

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-(methylsulfonyl)pyrimidine. MS (ESI): mass calcd. for C₃₂H₂₈F₂N₈O₂, 594.23; m/z found, 595.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=5.7, 1H), 8.36 (d, J=4.4, 2H), 7.95 (d, J=8.4, 2H), 7.61-7.52 (m, 2H), 7.06-6.99 (m, 2H), 6.81 (d, J=5.6, 1H), 3.61-3.41 (m, 2H), 2.20-1.89 (m, 1 OH), 1.78 (d, J=12.3, 2H).

Example 225

7-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in a manner similar to that described in Example 69 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 2-chloropyrimidine. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₂, 378.15; m/z found, 379.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.63-8.58 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.62 (m, 1H), 7.46-7.39 (m, 1H), 7.34-7.28 (m, 1H), 7.28-7.23 (m, 1H), 4.39-4.33 (m, 2H), 3.73-3.59 (m, 3H), 2.24-2.08 (m, 4H), 2.04-1.93 (m, 1H), 1.87-1.76 (m, 1H).

Example 226

2-(6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy)pyrimidin-4-amine

The title compound was prepared in a manner similar to that described in Example 69 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 2-chloro-4-aminopyrimidine. MS (ESI): mass calcd. for C₂₁H₂₀FN₅O₂, 393.16; m/z found, 394.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.05-8.00 (m, 1H), 7.76-7.72 (m, 1H), 7.64-7.61 (m, 1H), 7.51-7.45 (m, 1H), 7.36-7.31 (m, 1H), 6.50-6.45 (m, 1H), 4.39-4.33 (m, 2H), 3.74-3.64 (m, 3H), 2.33-2.23 (m, 2H), 2.23-2.14 (m, 2H), 2.11-2.01 (m, 1H), 1.91-1.83 (m, 1H).

Example 227

7-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in a manner similar to that described in Example 69 using 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol and 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₃, 408.16; m/z found, 409.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.35-8.30 (m, 1H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 1H), 7.46-7.39 (m, 1H), 7.34-7.27 (m, 1H), 6.44-6.39 (m, 1H), 4.40-4.31 (m, 2H), 4.05-3.97 (m, 3H), 3.74-3.67 (m, 2H), 3.67-3.54 (m, 1H), 2.28-2.09 (m, 4H), 2.06-1.93 (m, 1H), 1.87-1.78 (m, 1H).

Example 228

5-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl-1H-pyrrolo[2,3-I]pyridine

The title compound was prepared in a manner similar to that described in Example 69 using 6-cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol and 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O₂, 390.15; m/z found, 391.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.51-8.44 (m, 2H), 8.38-8.33 (m, 1H), 7.61-7.56 (m, 1H), 7.54-7.47 (m, 1H), 7.38-7.31 (m, 1H), 6.77-6.71 (m, 1H), 6.45-6.39 (m, 1H), 4.03-3.98 (m, 3H), 3.70-3.59 (m, 1H), 2.28-2.13 (m, 4H), 2.08-1.96 (m, 1H), 1.89-1.79 (m, 1H).

Example 229

2-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared in a manner similar to that described in Example 69 using 6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol and 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₂₁H₁₈FN₅O₂, 391.14; m/z found, 392.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.61-8.57 (m, 1H), 8.38-8.34 (m, 1H), 7.87-7.84 (m, 1H), 7.83-7.77 (m, 1H), 7.40-7.35 (m, 1H), 6.74-6.69 (m, 1H), 6.43-6.40 (m, 1H), 4.03-3.98 (m, 3H), 3.71-3.60 (m, 1H), 2.26-2.15 (m, 4H), 2.08-1.97 (m, 1H), 1.89-1.81 (m, 1H).

Example 230

2-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared in a manner similar to that described in Example 69 using 6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol and 2-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.65-8.61 (m, 2H), 8.60-8.56 (m, 1H), 7.86-7.83 (m, 1H), 7.82-7.76 (m, 1H), 7.39-7.35 (m, 1H), 7.28-7.23 (m, 1H), 6.74-6.69 (m, 1H), 3.75-3.64 (m, 1H), 2.26-2.15 (m, 4H), 2.06-1.95 (m, 1H), 1.88-1.78 (m, 1H).

Example 232

6-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol and 2-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13; m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.64-8.59 (m, 2H), 8.16-8.10 (m, 1H), 7.76-7.70 (m, 1H), 7.58-7.53 (m, 1H), 7.39-7.34 (m, 1H), 7.29-7.24 (m, 1H), 3.74-3.62 (m, 1H), 2.26-2.09 (m, 4H), 2.06-1.94 (m, 1H), 1.87-1.77 (m, 1H).

Example 232

6-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂, 367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.29-8.26 (m, 1H), 8.15-8.10 (m, 1H), 7.76-7.70 (m, 1H), 7.57-7.53 (m, 1H), 7.39-7.35 (m, 1H), 5.84-5.81 (m, 1H), 3.74-3.61 (m, 1H), 3.53-3.47 (m, 3H), 2.35-2.24 (m, 2H), 2.23-2.14 (m, 2H), 2.10-1.99 (m, 1H), 1.90-1.81 (m, 1H).

Example 233

6-(3-(6-Aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidin-4-ol

The title compound was prepared in a manner similar to that described in Example 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O₂, 353.13; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.15-8.11 (m, 1H), 8.08-8.05 (m, 1H), 7.76-7.71 (m, 1H), 7.57-7.52 (m, 1H), 7.41-7.35 (m, 1H), 5.81-5.76 (m, 1H), 3.74-3.63 (m, 1H), 2.34-2.24 (m, 2H), 2.24-2.14 (m, 2H), 2.10-2.01 (m, 1H), 1.91-1.82 (m, 1H).

Example 234

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidine-2-carbonitrile

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloropyrimidine-2-carbonitrile. ¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 1H), 8.76-8.72 (m, 1H), 8.53 (d, J=6.1, 1H), 8.00 (d, J=6.1, 1H), 7.38-7.30 (m, 1H), 7.12 (d, J=8.1, 1H), 3.89-3.77 (m, 1H), 2.42-2.32 (m, 2H), 2.24-2.14 (m, 2H), 2.11-2.00 (m, 1H), 1.92-1.83 (m, 1H).

Example 235

6-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N,2-trimethylpyrimidin-4-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 6-chloro-N,N,2-trimethylpyrimidin-4-amine. MS (ESI): mass calcd. for C₂₁H₂₃FN₆O, 394.19; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.30-8.25 (m, 1H), 8.11 (d, J=1.5, 1H), 7.89-7.82 (m, 1H), 7.38 (d, J=8.0, 1H), 5.74 (s, 1H), 3.71-3.61 (m, 1H), 3.17 (s, 6H), 2.53 (s, 3H), 2.34-2.18 (m, 4H), 2.13-2.00 (m, 1H), 1.94-1.83 (m, 1H).

Example 236

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy-N,N,6-trimethylpyrimidin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-N,N,6-trimethylpyrimidin-2-amine. MS (ESI): mass calcd. for C₂₁H₂₃FN₆O, 394.19; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25-8.22 (m, 1H), 8.12 (d, J=1.5, 1H), 7.82 (t, J=7.9, 1H), 7.33 (d, J=8.3, 1H), 6.65 (d, J=0.7, 1H), 3.67-3.57 (m, 1H), 3.19-2.95 (m, 5H), 2.56 (d, J=0.6, 3H), 2.30-2.15 (m, 4H), 2.08-1.99 (m, 1H), 1.91-1.81 (m, 1H).

Example 237

6-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N-dimethylpyrimidin-4-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 6-chloro-N,N-dimethylpyrimidin-4-amine. MS (ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J=1.4, 1H), 8.23-8.18 (m, 2H), 7.86-7.79 (m, 1H), 7.32 (d, J=8.1, 1H), 6.11 (d, J=0.6, 1H), 3.70-3.59 (m, 1H), 3.14 (d, J=10.6, 6H), 2.29-2.14 (m, 4H), 2.08-1.95 (m, 1H), 1.90-1.80 (m, 1H).

Example 238

Ethyl 5-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and ethyl 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate. MS (ESI): mass calcd. for C₂₂H₂₁F₄N₅O₃, 479.16; m/z found, 480.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J=1.4, 1H), 8.11 (d, J=1.6, 1H), 7.71-7.64 (m, 1H), 7.32 (d, J=8.3, 1H), 3.99-3.86 (m, 6H), 2.42-2.23 (m, 4H), 2.16-2.05 (m, 1H), 1.96-1.87 (m, 1H), 0.98 (t, J=7.1, 3H).

Example 239

5-(4-Cyclobutyl-2-fluoro-3-((5-(methylsulfonyl)pyridin-2-yl)oxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-5-(methylsulfonyl)pyridine. MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.61-8.59 (m, 1H), 8.37-8.33 (m, 1H), 8.25 (d, J=1.4, 1H), 8.19 (s, 1H), 7.85-7.78 (m, 1H), 7.33-7.29 (m, 2H), 3.68-3.56 (m, 1H), 3.18 (s, 3H), 2.23-2.12 (m, 4H), 2.04-1.93 (m, 1H), 1.86-1.77 (m, 1H).

Example 240

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-(tert-butyl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-(tert-butyl)-6-chloropyrimidin-2-amine. MS (ESI): mass calcd. for C₂₂H₂₅FN₆O, 408.21; m/z found, 409.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.23 (m, 1H), 8.10 (d, J=1.5, 1H), 7.79 (t, J=7.9, 1H), 7.31 (d, J=8.2, 1H), 6.76 (s, 1H), 3.69-3.59 (m, 1H), 2.30-2.15 (m, 4H), 2.09-1.98 (m, 1H), 1.91-1.82 (m, 1H), 1.44 (s, 9H).

Example 241

5-(3-((4-(1,5-Dioxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 9-(2-chloropyrimidin-4-yl)-1,5-dioxa-9-azaspiro[5.5]undecane. MS (ESI): mass calcd. for C₂₆H₂₉FN₆O₃, 492.23; m/z found, 493.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 1H), 8.16 (s, 1H), 8.11 (d, J=7.4, 1H), 7.86 (t, J=7.9, 1H), 7.36 (d, J=8.3, 1H), 6.89-6.86 (m, 1H), 3.87 (t, J=5.5, 4H), 3.74-3.57 (m, 5H), 2.35-2.16 (m, 4H), 2.12-2.02 (m, 1H), 1.96-1.63 (m, 7H).

Example 242

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-isobutylpyrimidin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-isobutylpyrimidin-2-amine. MS (ESI): mass calcd. for C₂₂H₂₅FN₆O, 408.21; m/z found, 409.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.26 (s, 1H), 8.07 (d, J=1.4, 1H), 7.77 (t, J=7.9, 1H), 7.28 (d, J=8.3, 1H), 6.66 (s, 1H), 3.68-3.57 (m, 1H), 2.65 (d, J=7.4, 2H), 2.30-2.23 (m, 2H), 2.21-2.15 (m, 2H), 2.13-2.08 (m, 1H), 2.07-2.01 (m, 1H), 1.91-1.83 (m, 1H), 1.05 (d, J=6.6, 6H).

Intermediate I

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine

To a 5 mL microwave vial were added a stir bar, 5-bromo-7-azaindole (59 mg, 0.30 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (74 mg, 0.33 mmol), 14.7 mg Pd(dppf)Cl₂.CH₂Cl₂ (15 mg, 0.18 mmol) and K₂CO₃ (129 mg, 0.93 mmol). The vial was flushed with nitrogen and then charged with sparged toluene (0.50 mL), sparged water (0.50 mL) and sparged DMF (0.30 mL). The vial was heated at 80° Celsius for 24 hours before cooling to room temperature, diluting the reaction mixture with DCM, drying the mixture over MgSO₄ filtering through a plug of diatomacious earth and concentrating to dryness. The dark residue was subjected to FCC to give the title compound as a white solid (67 mg, 76%). MS (ESI): mass calcd. for C₁₈H₁₇N₂FO 296.13, m/z found 297.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 9.88 (s, 1H), 8.52-8.46 (m, 1H), 8.13-8.09 (m, 1H), 7.42-7.37 (dd, J=3.5, 2.3, 1H), 7.21-7.16 (m, 1H), 7.16-7.11 (m, 1H), 6.59-6.54 (dd, J=3.5, 1.9, 1H), 3.93 (s, 3H), 3.89-3.79 (m, 1H), 2.43-2.34 (m, 2H), 2.24-2.14 (m, 2H), 2.13-2.02 (m, 1H), 1.93-1.85 (m, 1H).

Example 243

N-(2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-ethyl)-methane-sulfonamide

A mixture of N-(2-chloroethyl)methanesulfonamide (146 mg, 0.93 mmol), 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (200 mg, 0.77 mmol), Cs₂CO₃ (376 mg, 1.16 mmol) and DMF (6 mL) was stirred at room temperature for 16 hours, and then treated with water (10 mL). The mixture was extracted with EtOAc (3×20 ml). The combined organic phases were dried, concentrated to dryness, and the residue purified using FCC to give the title compound (165 mg, 56%). MS (CI): mass calcd. for C₂₁H₂₁FN₄O₃S, 380.13; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.08 (s, 1H), 7.55 (m, 1H), 7.15 (d, J=8.2 Hz, 1H), 5.44-5.26 (m, 1H), 4.78 (s, 2H), 4.10 (t, J=4.9 Hz, 2H), 3.84-3.69 (m, 1H), 3.60-3.49 (m, 2H), 3.05 (s, 3H), 2.42-2.27 (m, 2H), 2.22-2.01 (m, 3H), 1.94-1.80 (m, 1H).

Example 244

5-(4-Cyclobutyl-2-fluoro-3-(2-morpholinoethoxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 243 using 4-(2-bromoethyl)morpholine. MS (CI): mass calcd. for C₂₀H₂₅FN₄O₂, 372.20; m/z found, 373.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.42 (m, 1H), 8.09 (d, J=1.4, 1H), 7.54 (m, 1H), 7.15 (d, J=8.2, 1H), 4.74 (s, 2H), 4.18 (t, J=5.3, 2H), 3.84 (dd, J=18.0, 6.6, 5H), 2.89 (s, 2H), 2.70 (s, 4H), 2.39-2.32 (m, 2H), 2.20-2.12 (m, 2H), 2.08-2.01 (m, 1H), 1.88 (d, J=10.4, 1H).

Example 245

Ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate

The title compound was prepared using analogous conditions described in Example 243 using ethyl 4-bromobutanoate. MS (CI): mass calcd. for C₂₀H₂₄FN₃O₃, 373.18; m/z found, 374.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.52-8.38 (m, 1H), 8.08 (d, J=1.6, 1H), 7.53 (m, 1H), 7.14 (d, J=8.2, 1H), 4.65 (s, 2H), 4.17 (q, J=7.2, 2H), 4.04 (t, J=6.2, 2H), 3.86-3.75 (m, 1H), 2.59 (t, J=7.4, 2H), 2.39-2.30 (m, 2H), 2.20-2.03 (m, 5H), 1.87 (ddd, J=11.3, 10.3, 8.7, 1H), 1.28 (t, J=7.1, 3H).

Example 246

tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)azetidine-1-carboxylate

The title compound was prepared using analogous conditions described in Example 243 using tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate. MS (CI): mass calcd. for C₂₃H₂₉FN₄O₃, 428.22; m/z found, 429.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.09 (d, J=1.2, 1H), 7.54 (m, 1H), 7.15 (d, J=8.2, 1H), 4.70 (s, 2H), 4.16 (d, J=6.5, 2H), 4.09 (t, J=8.5, 2H), 3.90-3.83 (m, 2H), 3.82-3.73 (m, 1H), 3.04-2.92 (m, 1H), 2.40-2.28 (m, 2H), 2.21-2.01 (m, 3H), 1.92-1.83 (m, 1H), 1.45 (s, 9H).

Example 247

tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared using analogous conditions described in Example 243 using tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate. MS (CI): mass calcd. for C₂₄H₃₁FN₄O₃, 442.24; m/z found, 465.2 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48-8.43 (m, 1H), 8.09 (d, J=1.5, 1H), 7.53 (m, 1H), 7.14 (d, J=8.3, 1H), 4.65 (s, 2H), 4.04-3.91 (m, 2H), 3.86-3.75 (m, 1H), 3.69-3.34 (m, 3H), 3.29-3.25 (m, 1H), 2.71-2.63 (m, 1H), 2.38-2.31 (m, 2H), 2.19-2.03 (m, 4H), 1.92-1.76 (m, 2H), 1.48 (s, 9H).

Example 248

tert-Butyl 2-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared using analogous conditions described in Example 243 using tert-butyl 2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate. MS (CI): mass calcd. for C₂₄H₃₁FN₄O₃, 442.24; m/z found, 443.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.08 (s, 1H), 7.55 (s, 1H), 7.13 (s, 1H), 4.64 (s, 2H), 4.09 (s, 2H), 3.85-3.77 (m, 2H), 3.42 (s, 2H), 2.39-2.25 (m, 3H), 2.18-1.98 (m, 5H), 1.92-1.81 (m, 2H), 1.44 (s, 9H).

Example 249

tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)piperidine-1-carboxylate

The title compound was prepared using analogous conditions described in Example 243 using tert-butyl 2-(bromomethyl)piperidine-1-carboxylate. MS (CI): mass calcd. for C₂₅H₃₃FN₄O₃, 456.25; m/z found, 457.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (m, 1H), 8.09 (m, 1H), 7.52 (m, 1H), 7.14 (d, J=8.2, 1H), 4.63 (s, 2H), 4.30-4.18 (m, 1H), 4.04-3.93 (m, 1H), 3.91-3.85 (m, 2H), 3.83-3.75 (m, 1H), 2.88-2.72 (m, 2H), 2.41-2.30 (m, 2H), 2.24-1.96 (m, 5H), 1.95-1.80 (m, 2H), 1.76-1.67 (m, 1H), 1.57-1.50 (m, 1H), 1.48 (s, 9H).

Example 250

2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)ethanol

The title compound was prepared using analogous conditions described in Example 243 using 2-(2-bromoethoxy)tetrahydro-2H-pyran. The initial alkylation product was treated with a 0.2 M methanolic HCl, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the residue was subjected to FCC to obtain the titled compound. MS (CI): mass calcd. for C₁₆H₁₈FN₃O₂, 303.14; m/z found, 304.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=1.6, 1H), 7.99 (d, J=1.4, 1H), 7.50 (t, J=7.9, 1H), 7.20 (d, J=8.2, 1H), 6.64 (s, 2H), 4.86 (t, J=5.5, 1H), 3.98 (t, J=5.0, 2H), 3.85 (dd, J=17.8, 8.8, 1H), 3.70 (dd, J=10.4, 5.2, 2H), 2.30 (ddd, J=13.8, 8.3, 5.8, 2H), 2.14-2.05 (m, 2H), 2.02-1.95 (m, 1H), 1.82 (dd, J=18.6, 9.3, 1H).

Example 251

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoic acid

Ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate (300 mg, 0.8 mmol) was dissolved in THF (6 ml), then a solution of LiOH.H2O (101 mg, 2.41 mmol) and water (2 ml) was added. The reaction was stirred overnight, then the mixture was acidified to pH=7 by adding 1M HCl. The mixture was concentrated to dryness and subjected to FCC to give the title compound (135 mg. 45%). MS (CI): mass calcd. for C₁₈H₂₀FN₃O₃, 345.15; m/z found, 346.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 8.38-8.29 (m, 1H), 8.05 (d, J=1.6, 1H), 7.56 (m, 1H), 7.26 (d, J=8.2, 1H), 6.70 (s, 2H), 4.02 (t, J=6.4, 2H), 3.87-3.77 (m, 1H), 2.50 (t, J=7.3, 2H), 2.40-2.30 (m, 2H), 2.20-1.99 (m, 5H), 1.92-1.83 (m, 1H).

Example 252

5-(4-Cyclobutyl-2-fluoro-3-((tetrahydrofuran-2-yl)methoxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 243 using 2-(bromomethyl)tetrahydro-[2H]-pyran at 60° Celsius. MS (CI): mass calcd. for C₁₉H₂₂FN₃O₂, 343.17; m/z found, 344.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.56-8.37 (m, 1H), 8.08 (d, J=1.5, 1H), 7.53 (dd, J=10.2, 5.4, 1H), 7.15 (d, J=8.3, 1H), 4.62 (s, 2H), 4.34-4.21 (m, 1H), 4.08-4.03 (m, 1H), 4.00-3.81 (m, 4H), 2.41-2.32 (m, 2H), 2.17-1.82 (m, 8H).

Example 253

Racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(isobutylamino)propan-2-ol Step A: 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 243 heating at 60° Celsius using (rac)-epichlorohydrin. ¹H NMR (400 MHz, CDCl₃) δ 8.57-8.40 (m, 1H), 8.08 (d, J=1.5, 1H), 7.54 (dd, J=14.2, 6.6, 1H), 7.15 (d, J=8.2, 1H), 4.64 (s, 2H), 4.28 (dd, J=11.2, 3.2, 1H), 3.98 (dd, J=11.2, 6.1, 1H), 3.92-3.81 (m, 1H), 3.38 (td, J=6.4, 3.2, 1H), 2.92-2.86 (m, 1H), 2.72 (dd, J=5.0, 2.6, 1H), 2.43-2.34 (m, 2H), 2.20-2.01 (m, 3H), 1.93-1.83 (m, 1H).

Step B: 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(isobutylamino)-propan-2-ol

A mixture of 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (150 mg, 0.48 mmol), isobutylamine (105 mg, 1.43 mmol) and MeOH (5 mL) was heated in sealed tube to 60° Celsius for 5 hours, then the solvent was removed. The residue was subjected to FCC to give the titled compound (125 mg, 67%). MS (CI): mass calcd. for C₂₁H₂₉FN₄O₂, 388.23; m/z found, 389.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48-8.39 (m, 1H), 8.08 (d, J=1.4, 1H), 7.54 (m, 1H), 7.14 (d, J=8.2, 1H), 4.72 (s, 2H), 4.45-4.37 (m, 1H), 4.09-3.99 (m, 2H), 3.86-3.73 (m, 1H), 3.29-3.21 (m, 1H), 3.16-3.07 (m, 1H), 2.86-2.69 (m, 2H), 2.41-2.30 (m, 2H), 2.19-2.01 (m, 4H), 1.90-1.81 (m, 1H), 1.05 (d, J=6.7, 6H).

Example 254

Racemic 3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propane-1,2-diol

The title compound is a side product found when water opens the epoxide, 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine, using the conditions in Example 253 Step B. MS (CI): mass calcd. for C₁₇H₂₀FN₃O₃, 333.15; m/z found, 334.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.99 (d, J=1.4, 1H), 7.50 (m, 1H), 7.20 (d, J=8.2, 1H), 6.64 (s, 2H), 4.93 (d, J=5.1, 1H), 4.64 (t, J=5.6, 1H), 4.02-3.97 (m, 1H), 3.92-3.83 (m, 2H), 3.82-3.77 (m, 1H), 3.46 (t, J=5.6, 2H), 2.35-2.27 (m, 2H), 2.14-1.95 (m, 3H), 1.86-1.78 (m, 1H).

Example 255

Racemic 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-morpholinopropan-2-ol

The title compound was prepared using analogous conditions described in Example 253 using morpholine in Step B. MS (CI): mass calcd. for C₂₁H₂₇FN₄O₃, 402.21; m/z found, 403.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48-8.44 (m, 1H), 8.09 (d, J=1.5, 1H), 7.58-7.53 (m, 1H), 7.16 (d, J=8.2, 1H), 4.67 (s, 2H), 4.18 (s, 1H), 4.03 (d, J=4.9, 2H), 3.88-3.83 (m, 1H), 3.79 (s, 4H), 2.76 (s, 2H), 2.68 (s, 2H), 2.60 (s, 2H), 2.40-2.33 (m, 2H), 2.17 (dt, J=9.3, 5.4, 2H), 2.09-2.00 (m, 1H), 1.93-1.84 (m, 1H)

Example 256

Racemic 4-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)thiomorpholine 1,1-dioxide

The title compound was prepared using analogous conditions described in Example 253 using thiomorpholine 1,1-dioxide in Step B. MS (CI): mass calcd. for C₂₁H₂₇FN₄O₄S, 450.17; m/z found, 451.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.98 (m, 1H), 7.48 (m, 1H), 7.18 (d, J=8.2, 1H), 6.62 (s, 2H), 4.94 (d, J=4.4, 1H), 3.96-3.79 (m, 4H), 3.12-3.03 (m, 4H), 3.02-2.95 (m, 4H), 2.68 (dd, J=13.2, 4.3, 1H), 2.61-2.52 (m, 1H), 2.31-2.23 (m, 2H), 2.13-1.92 (m, 3H), 1.83-1.73 (m, 1H).

Example 257

5-(4-Cyclobutyl-2-fluoro-3-(pyridazin-4-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 with DMSO as the solvent, heating for 2 hours at 80° Celsius via microwave radiation and substituting Intermediate B and 4-bromo-pyridazine hydrobromide. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13; m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.12-9.05 (m, 1H), 9.01-8.95 (m, 1H), 8.47-8.41 (m, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.91-7.82 (m, 1H), 7.35-7.28 (m, 1H), 6.83-6.75 (m, 1H), 4.84 (s, 2H), 3.63-3.49 (m, 1H), 2.28-2.06 (m, 4H), 2.08-1.90 (m, 1H), 1.90-1.79 (m, 1H).

Example 258

3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 with DMSO as the solvent, heating for 2 hours at 140° Celsius via microwave radiation and substituting Intermediate B and 2-amino-3-chloropyrazine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29-8.23 (m, 3H), 8.01 (d, J=1.5 Hz, 3H), 7.76-7.68 (m, 3H), 7.61 (d, J=3.0 Hz, 3H), 7.28 (d, J=8.3 Hz, 3H), 7.14 (d, J=3.0 Hz, 3H), 6.70 (s, 11H), 3.62-3.49 (m, 3H), 2.17-2.00 (m, 12H), 1.98-1.83 (m, 3H), 1.81-1.67 (m, 3H).

Example 259

5-(4-Cyclobutyl-2-fluoro-3-(pyrazin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 160 with DMSO as the solvent, heating for 2 hours at 80° Celsius via microwave radiation and substituting Intermediate B and 2-fluoropyrazine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13; m/z found, 337.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J=1.3 Hz, 1H), 8.49-8.42 (m, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.12-8.03 (m, 2H), 7.85-7.76 (m, 1H), 7.23 (s, 1H), 4.70 (s, 2H), 3.68-3.56 (m, 1H), 2.26-2.08 (m, 4H), 2.03-1.89 (m, 1H), 1.87-1.76 (m, 1H).

Example 260

5-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-4-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 with pyridine as a solvent, heating at 80° Celsius for 18 hours and substituting 4-chloropyrimidine hydrochloride. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13 m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.62 (d, J=5.8 Hz, 1H), 8.47-8.45 (m, 1H), 8.09 (d, J=1.4 Hz, 1H), 7.82 (m, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.02 (dd, J=5.8, 1.0 Hz, 1H), 4.67 (s, 2H), 3.59 (m, 1H), 2.25-2.08 (m, 4H), 2.03-1.89 (m, 1H), 1.86-1.76 (m, 1H).

Example 261

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N-isobutylpyrimidin-2-amine trifluoroacetic acid salt Step A: 5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

Example 137 was prepared using conditions similar to those described in Example 101 with DMSO as a solvent, heating via microwave irradiation at 120° Celsius for 1 hour and using 2,4-dichloropyrimidine.

Step B

The crude material from Step A was treated with 10 equivalents of isobutylamine and heated via microwave irradiation at 140° Celsius for 1 hour. The resulting mixture was subjected to FCC followed by reverse phase HPLC to give 6 mg (6%) of the title compound. MS (ESI): mass calcd. for C₂₂H₂₅FN₆O, 408.21 m/z found, 409.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.38-10.29 (m, 1H), 8.38 (d, J=1.1 Hz, 1H), 8.22 (s, 1H), 7.99 (d, J=6.8 Hz, 1H), 7.96-7.88 (m, 1H), 7.31-7.23 (m, 1H), 6.46 (d, J=6.8 Hz, 1H), 3.63-3.49 (m, 1H), 2.94-2.84 (m, 2H), 2.31-1.96 (m, 4H), 1.93-1.81 (m, 1H), 1.68-1.54 (m, 1H), 0.66 (d, J=6.7 Hz, 6H).

Example 262

Methyl-2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-benzoxazole-5-carboxylate

The title compound was prepared using analogous conditions described in Example 69 using methyl 2-(chloromethyl)benzo[d]oxazole-5-carboxylate. MS (ESI): mass calcd. for C₂₄H₂₁FN₄O₄, 448.15; m/z found, 449.1 [M+H]⁺.

Example 263

Methyl 3-({[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetyl}amino)-4-hydroxybenzoate

Title compound was a side product from the preparation of Example 262. MS (ESI): mass calcd. for C₂₄H₂₃FN₄O₅, 466.17; m/z found, 467.1 [M+H]⁺.

Example 264

5-[4-Cyclobutyl-2-fluoro-3-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 69 using 4-bromomethyltetrahydropyran. MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₂, 357.19; m/z found, 358.1 [M+H]⁺.

Example 265

4-[3-(5-Aminopyrazin-2-yl-6-cyclobutyl-2-fluorophenoxy]-3-(methylsulfonyl)benzonitrile

The title compound was prepared using analogous conditions described in Example 69 using 4-fluoro-3-(methylsulphonyl)benzonitrile. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O₃, 438.12; m/z found, 439.1 [M+H]⁺.

Example 266

5-{3-[2,4-Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 69 using 2,4-bis-(trifluoromethyl)fluorobenzene. MS (ESI): mass calcd. for C₂₂H₁₆F₇N₃O, 471.12; m/z found, 472.1 [M+H]⁺.

Example 267

5-{4-Cyclobutyl-3-[3-(dimethylamino)propoxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 243 utilizing 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. MS (ESI): mass calcd. for C₁₉H₂₅FN₄O, 344.20; m/z found, 345.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.09 (d, J=1.3, 1H), 7.53 (m, 1H), 7.14 (d, J=8.2, 1H), 4.73 (s, 2H), 4.06 (t, J=6.0, 2H), 3.88-3.71 (m, 1H), 2.90-2.75 (m, 2H), 2.47 (s, 6H), 2.36-2.32 (m, 2H), 2.20-2.02 (m, 5H), 1.89-1.84 (m, 1H).

Example 268

5-{4-Cyclobutyl-3-[2-(dimethylamino)ethoxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 243 utilizing 2-chloro-N,N-dimethylethanamine hydrochloride. MS (ESI): mass calcd. for C₁₈H₂₃FN₄O, 330.19; m/z found, 331.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.52-8.39 (m, 1H), 8.09 (d, J=1.5, 1H), 7.56 (m, 1H), 7.16 (d, J=8.4, 1H), 4.64 (s, 2H), 4.25 (s, 2H), 3.84-3.79 (m, 1H), 3.06 (s, 2H), 2.64 (s, 6H), 2.41-2.31 (m, 2H), 2.23-2.02 (m, 3H), 1.93-1.83 (m, 1H).

Example 269

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,6-dimethylpyrimidin-2-amine

The title compound was prepared using analogous conditions described in Example 69 using 4-chloro-N,6-dimethylpyrimidin-2-amine. MS (ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.2 [M+H]⁺.

Example 270

2-[6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenoxy]pyrimidin-4-amine

The title compound was prepared using analogous conditions described in Example 69 using 4-amino-2-chloropyrimidine and 6-cyclobutyl-2-fluoro-3-{7-[(4-methylphenyl)-sulfonyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}phenol. MS (ESI): mass calcd. for C₂₀H₁₇FN₆O, 376.14; m/z found, 376.9 [M+H]⁺.

Example 271

5-{4-Cyclobutyl-3-[(6,7-difluoroquinoxalin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloro-6,7-difluoroquinoxaline. MS (ESI): mass calcd. for C₂₂H₁₆F₃N₅O, 423.13; m/z found, 424.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.86 (s, 1H), 8.31-8.21 (m, 1H), 8.06 (dd, J=1.5, 0.7, 1H), 7.94 (dd, J=10.7, 8.3, 1H), 7.82-7.75 (m, 1H), 7.59 (dd, J=11.1, 8.1, 1H), 7.33 (d, J=8.3, 1H), 3.78-3.54 (m, 1H), 2.19 (t, J=8.9, 4H), 2.01-1.93 (m, 1H), 1.85-1.77 (m, 1H).

Example 272

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]quinazolin-4-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloroquinazolin-4-amine. MS (ESI): mass calcd. for C₂₂H₁₉FN₆O, 402.16; m/z found, 403.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.29 (d, J=2.1, 1H), 8.10-7.97 (m, 2H), 7.69 (dd, J=13.1, 6.9, 2H), 7.55 (d, J=8.5, 1H), 7.41-7.33 (m, 1H), 7.26 (d, J=8.3, 1H), 3.71 (t, J=9.0, 1H), 2.28-2.08 (m, 4H), 2.02-1.92 (m, 1H), 1.81 (d, J=9.6, 1H).

Example 273

2-Amino-5-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carbonitrile

The title compound was prepared using analogous conditions described in Example 69 using 2-amino-5-bromopyrimidine-4-carbonitrile. MS (ESI): mass calcd. for C₁₉H₁₆FN₇O, 377.14; m/z found, 377.9 [M+H]⁺.

Example 274

Methyl 2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-benzoxazole-5-carboxylate

The title compound was prepared using analogous conditions described in Example 69 using methyl 2-(chloromethyl)benzo[d]oxazole-5-carboxylate. MS (ESI): mass calcd. for C₂₄H₂₁FN₄O₄, 448.15; m/z found, 449.1 [M+H]⁺.

Example 275

Methyl 3-({[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetyl}amino)-4-hydroxybenzoate

Title compound was a side product from the preparation of Example 274. MS (ESI): mass calcd. for C₂₄H₂₃FN₄O₅, 466.17; m/z found, 467.1 [M+H]⁺.

Example 276

[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetonitrile

The title compound was prepared using analogous conditions described in Example 69 using chloroacetonitrile. MS (ESI): mass calcd. for C₁₆H₁₅FN₄O, 298.12; m/z found, 299.1 [M+H]⁺.

Example 277

5-[4-Cyclobutyl-2-fluoro-3-(pyridazin-3-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 69 using 3-chloropyridazine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13; m/z found, 338.1 [M+H]⁺.

Example 278

5-[4-Cyclopropyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-bromopyrimidine and 3-(5-aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenol. MS (ESI): mass calcd. for C₁₇H₁₄FN₅O, 323.12; m/z found, 324.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.62 (d, J=4.8, 2H), 8.25 (dd, J=2.3, 1.5, 1H), 8.04 (d, J=1.5, 1H), 7.69-7.61 (m, 1H), 7.29-7.21 (m, 1H), 6.95-6.86 (m, 1H), 2.07-1.87 (m, 1H), 0.95-0.82 (m, 2H), 0.74-0.65 (m, 2H).

Example 279

2-[3-(5-Aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloropyrimidin-4-amine and 3-(5-aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenol. MS (ESI): mass calcd. for C₁₇H₁₅FN₆O, 338.13; m/z found, 339.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.31-8.22 (m, 1H), 8.03 (d, J=1.5, 1H), 7.88 (d, J=5.9, 1H), 7.65-7.57 (m, 1H), 6.85 (d, J=8.5, 1H), 6.25 (d, J=5.9, 1H), 2.02-1.91 (m, 1H), 0.91 (m, 2H), 0.75-0.68 (m, 2H).

Example 280

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-2-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

The title compound was prepared using analogous conditions described in Example 69 using 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.2 [M+H]⁺.

Example 281

Methyl 2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-oxazole-4-carboxylate Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using methyl 2-(chloromethyl)oxazole-4-carboxylate. MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₄, 398.14; m/z found, 399.1 [M+H]⁺.

Example 282

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-oxazole-4-carboxylic Acid Trifluoroacetic Acid Salt

Title compound was a side product obtained in the preparation of Example 284. MS (ESI): mass calcd. for C₁₉H₁₇FN₄O₄, 384.12; m/z found, 385.1 [M+H]⁺.

Example 283

5-[3-(1,3-Benzothiazol-2-ylmethoxy-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 2-(chloromethyl)benzo[d]thiazole. MS (ESI): mass calcd. for C₂₂H₁₉FN₄OS, 406.13; m/z found, 407.1 [M+H]⁺.

Example 284

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-4-yl)methoxy]phenyl}pyrazin-2-amine Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.1 [M+H]⁺.

Example 285

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-5-yl)methoxy]phenyl}pyrazin-2-amine Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 5-(chloromethyl)-1-methyl-1H-imidazolehydrochloride. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.1 [M+H]⁺.

Example 286

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclo butyl-2-fluorophenoxy]methyl}pyridine-3-carbonitrile Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 2-(chloromethyl)nicotinonitrile. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 375.15; m/z found, 354.1 [M+H]⁺.

Example 287

5-{4-Cyclobutyl-2-fluoro-3-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl}pyrazin-2-amine Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 4-(chloromethyl)-2-methylthiazole. MS (ESI): mass calcd. for C₁₉H₁₉FN₄OS, 370.13; m/z found, 371.0 [M+H]⁺.

Example 288

5-[4-Cyclobutyl-2-fluoro-3-(pyridazin-3-ylmethoxy)phenyl]pyrazin-2-amine Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 3-(chloromethyl)pyridazine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺.

Example 289

5-{3-[(5-Chloropyridin-2-yl)methoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 5-chloro-2-(chloromethyl)pyridine. MS (ESI): mass calcd. for C₂₀H₁₈FClN₄O, 384.12; m/z found, 385.0 [M+H]⁺.

Example 290

5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}pyridine-2-carbonitrile Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 5-(chloromethyl)picolinonitrile. MS (ESI): mass calcd. for C₂₁H₁₈FN₅O, 375.15; m/z found, 376.1 [M+H]⁺.

Example 291

5-{4-Cyclobutyl-2-fluoro-3-[(5-methylisoxazol-3-yl)methoxy]phenyl}pyrazin-2-amine Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 3-(chloromethyl)-5-methylisoxazole. MS (ESI): mass calcd. for C₁₉H₁₉FN₄O₂, 354.15; m/z found, 355.1 [M+H]⁺.

Example 292

6-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}pyridine-2-carbonitrile Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 69 using 6-(chloromethyl)picolinonitrile. MS (ESI): mass calcd. for C₂₁H₁₈FN₅O, 375.15; m/z found, 376.0 [M+H]⁺.

Example 293

2-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}-1H-isoindole-1,3(2H)-dione

The title compound was prepared using analogous conditions described in Example 69 using 2-(2-bromoethyl)isoindoline-1,3-dione. MS (ESI): mass calcd. for C₂₄H₂₁FN₄O₃, 432.16; m/z found, 433.0 [M+H]⁺.

Example 294

5-[3-(2-Aminoethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine

To a 200 mL round-bottomed flask containing 2-{2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}-1H-isoindole-1,3(2H)-dione (550 mg, 1.27 mmol) were added a stir bar and EtOH (26 mL). The mixture was then thoroughly sparged (bubbling N₂) before charging the flask with hydrazine monohydrate (1.00 mL, 21 mmol). The flask was then heated at 77° Celsius for 22 hours. The reaction mixture was cooled to rt, diluted with EtOAc, washed with NaOH (1 N, ×3), dried over MgSO4, filtered and concentrated to dryness to give the desired product (365 mg, 95%). MS (ESI): mass calcd. for C₁₆H₁₉FN₄O, 302.15; m/z found, 303.1 [M+H]⁺.

Example 295

5-{4-Cyclobutyl-2-fluoro-3-[2-(pyrazin-2-ylamino)ethoxy]phenyl}pyrazin-2-amine Trifluoroacetic Acid Salt

To a 5 mL microwave vial were added a spin-vane, 5-[3-(2-aminoethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine (47 mg, 0.16 mmol), 2-fluoropyrazine (35 mg, 0.35 mmol), and Cs₂CO₃ (115 mg, 0.35 mmol). The flask was thoroughly purged with nitrogen, charged with DMSO (1.0 mL), and heated at 100° Celsius for 14.5 hours before cooling to room temperature, filtering off the solids and subjecting the filtrate to HPLC purification to give the title compound (26 mg, 34%). MS (ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺.

Example 296

N-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}pyrimidin-2-amine Trifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described in Example 295 using 2-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺.

Example 297

N-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}pyrimidin-4-amine

The title compound was prepared using analogous conditions described in Example 295 using 4-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺.

Example 298

5-[4-Cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl]pyrazin-2-amine Hydrogen Chloride Salt

The title compound was prepared using analogous conditions described in Step A of Example 68 using tert-butyl 4-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)piperidine-1-carboxylate. MS (ESI): mass calcd. for C₂₀H₂₅FN₄O, 356.20; m/z found, 357.1 [M+H]⁺.

Example 299

Racemic 5-[4-Cyclobutyl-2-fluoro-3-(piperidin-3-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Step A of Example 68 utilizing racemic tert-butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)piperidine-1-carboxylate. MS (ESI): mass calcd. for C₂₀H₂₅FN₄O, 356.20; m/z found, 357.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 7.53 (m, 1H), 7.13 (d, J=8.2, 1H), 4.69 (s, 2H), 3.96-3.83 (m, 2H), 3.80-3.68 (m, 1H), 3.65-3.57 (m, 1H), 3.52-3.35 (m, 1H), 2.93-2.76 (m, 2H), 2.55-2.38 (m, 1H), 2.38-2.27 (m, 2H), 2.19-1.83 (m, 7H), 1.63-1.44 (m, 1H).

Example 300

Racemic 5-[4-Cyclobutyl-2-fluoro-3-(pyrrolidin-3-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Step A of Example 68 utilizing racemic tert-butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluoro-phenoxy)methyl)pyrrolidine-1-carboxylate. MS (ESI): mass calcd. for C₁₉H₂₃FN₄O, 342.19; m/z found, 343.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 8.43 (d, J=1.7, 1H), 8.08 (d, J=1.1, 1H), 7.53 (m, 1H), 7.14 (d, J=8.2, 1H), 4.73 (s, 2H), 4.12-3.97 (m, 2H), 3.78-3.64 (m, 2H), 3.55-3.39 (m, 2H), 3.38-3.28 (m, 1H), 2.99-2.81 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.01 (m, 4H), 1.92-1.83 (m, 1H).

Example 301

5-[3-(Azetidin-3-ylmethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Step A of Example 68 utilizing tert-butyl-3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)azetidine-1-carboxylate. MS (ESI): mass calcd. for C₁₈H₂₁FN₄O, 328.17; m/z found, 329.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.52 (m, 1H), 7.20 (d, J=8.2, 1H), 6.65 (s, 2H), 4.10 (d, J=5.7, 2H), 4.06-3.96 (m, 2H), 3.87-3.77 (m, 2H), 3.77-3.69 (m, 1H), 3.17-3.09 (m, 1H), 2.33-2.19 (m, 2H), 2.15-1.92 (m, 3H), 1.87-1.74 (m, 1H).

Example 302

Racemic 5-[4-Cyclobutyl-2-fluoro-3-(pyrrolidin-2-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Step A of Example 68 utilizing racemic tert-butyl 2-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate. MS (ESI): mass calcd. for C₁₉H₂₃FN₄O, 342.19; m/z found, 343.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=1.5, 1H), 7.97 (d, J=1.4, 1H), 7.49 (m, 1H), 7.19 (d, J=8.2, 1H), 6.63 (s, 2H), 3.98-3.88 (m, 2H), 3.85-3.76 (m, 1H), 3.59-3.52 (m, 1H), 3.01-2.91 (m, 2H), 2.32-2.24 (m, 2H), 2.17-1.89 (m, 5H), 1.84-1.70 (m, 3H), 1.61-1.51 (m, 1H).

Example 303

Racemic 5 1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-piperidin-1-ylpropan-2-ol

The title compound was prepared using analogous conditions described in Example 51 utilizing piperidine. MS (ESI): mass calcd. for C₂₂H₂₉FN₄O₂, 400.23; m/z found, 401.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.28-8.23 (m, 1H), 8.03 (d, J=1.5, 1H), 7.50 (m, 1H), 7.22 (d, J=8.2, 1H), 4.58 (s, 2H), 4.43-4.34 (m, 1H), 4.04-3.94 (m, 2H), 3.95-3.85 (m, 1H), 3.34 (dd, J=8.4, 4.9, 2H), 3.23 (d, J=13.2, 2H), 2.37 (m, 2H), 2.25-2.12 (m, 2H), 2.08 (m, 1H), 1.93-1.79 (m, 5H), 1.68 (s, 2H).

Example 304

Racemic 1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-(methylamino)propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 utilizing methylamine. MS (ESI): mass calcd. for C₁₈H₂₃FN₄O₂, 346.18; m/z found, 347.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.32-8.23 (m, 1H), 8.11-8.00 (m, 1H), 7.51 (m, 1H), 7.23 (d, J=8.2, 1H), 4.29-4.21 (m, 1H), 4.08-3.98 (m, 2H), 3.95-3.86 (m, 1H), 3.39-3.35 (m, 1H), 3.25-3.20 (m, 1H), 2.79 (s, 3H), 2.44-2.34 (m, 2H), 2.23-2.06 (m, 3H), 1.96-1.86 (m, 1H).

Example 305

Racemic 1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-[(1-methylethyl)amino]propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 utilizing isopropylamine. MS (ESI): mass calcd. for C₂₀H₂₇FN₄O₂, 374.21; m/z found, 375.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31-8.21 (m, 1H), 7.97 (d, J=1.4, 1H), 7.50 (m, 1H), 7.19 (d, J=8.2, 1H), 6.64 (s, 2H), 5.73 (s, 1H), 4.19-4.07 (m, 1H), 3.99-3.89 (m, 2H), 3.88-3.76 (m, 1H), 3.27-3.22 (m, 1H), 3.15-3.07 (m, 1H), 2.98-2.88 (m, 1H), 2.34-2.23 (m, 2H), 2.14-1.90 (m, 3H), 1.86-1.73 (m, 1H), 1.24-1.14 (m, 6H).

Example 306

Racemic 1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-pyrrolidin-1-ylpropan-2-ol

The title compound was prepared using analogous conditions described in Example 51 utilizing pyrrolidine. MS (ESI): mass calcd. for C₂₁H₂₇FN₄O₂, 386.21; m/z found, 387.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.54-8.36 (m, 1H), 8.09 (d, J=1.4, 1H), 7.55 (m, 1H), 7.15 (d, J=8.2, 1H), 4.71 (s, 2H), 4.23-4.12 (m, 1H), 4.02 (d, J=5.1, 2H), 3.94-3.78 (m, 1H), 3.20 (s, 1H), 2.99-2.92 (m, 1H), 2.91-2.83 (m, 2H), 2.78-2.68 (m, 3H), 2.42-2.31 (m, 2H), 2.21-2.01 (m, 3H), 1.93-1.81 (m, 5H).

Example 307

Racemic 1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-(dimethylamino)propan-2-ol

The title compound was prepared using analogous conditions described in Example 51 utilizing dimethylamine. MS (ESI): mass calcd. for C₁₉H₂₅FN₄O₂, 360.20; m/z found, 361.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.97 (d, J=1.4, 1H), 7.49 (m, 1H), 7.19 (d, J=8.2, 1H), 6.64 (s, 2H), 5.41 (s, 1H), 4.08 (s, 1H), 3.91-3.79 (m, 3H), 2.88-2.82 (m, 1H), 2.81-2.72 (m, 1H), 2.51 (s, 6H), 2.32-2.23 (m, 2H), 2.12-1.92 (m, 3H), 1.84-1.73 (m, 1H).

Example 308

Diastereomeric Mixture of 1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}pyrrolidin-3-ol

The title compound was prepared using analogous conditions described in Example 51 utilizing racemic 3-hydroxypyrrolidine. MS (ESI): mass calcd. for C₂₁H₂₇FN₄O₃, 402.21; m/z found, 403.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.23 (m, 1H), 7.97 (d, J=1.4, 1H), 7.48 (m, 1H), 7.19 (d, J=8.4, 1H), 6.63 (s, 2H), 5.46-5.14 (m, 1H), 4.96 (d, J=14.5, 1H), 4.28-4.21 (m, 1H), 4.06-3.98 (m, 1H), 3.93-3.79 (m, 3H), 3.07-2.64 (m, 6H), 2.33-2.24 (m, 2H), 2.13-1.94 (m, 4H), 1.86-1.75 (m, 1H), 1.70-1.57 (m, 1H).

Example 309

Racemic 1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-piperazin-1-ylpropan-2-ol

The title compound was prepared using analogous conditions described in Example 51 utilizing piperazine. MS (ESI): mass calcd. for C₂₁H₂₈FN₅O₂, 401.22; m/z found, 402.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.00 (d, J=1.4, 1H), 7.50 (m, 1H), 7.21 (d, J=8.3, 1H), 6.66 (s, 2H), 4.95 (s, 1H), 4.01-3.82 (m, 4H), 2.97 (t, J=4.9, 4H), 2.63 (s, 3H), 2.58-2.53 (m, 1H), 2.52-2.49 (m, 2H), 2.47-2.41 (m, 1H), 2.35-2.26 (m, 2H), 2.16-1.94 (m, 3H), 1.88-1.78 (m, 1H).

Example 310

Racemic 1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}pyrimidin-2(1H)-one

The title compound was prepared using analogous conditions described in Example 51 utilizing 2-pyrimidinone. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O₃, 411.17; m/z found, 412.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (dd, J=4.2, 2.8, 1H), 8.32-8.26 (m, 1H), 8.10 (dd, J=6.5, 2.8, 1H), 8.00 (d, J=1.5, 1H), 7.52 (m, 1H), 7.22 (d, J=8.3, 1H), 6.64 (s, 2H), 6.43 (dd, J=6.4, 4.2, 1H), 5.48 (d, J=5.8, 1H), 4.33 (dd, J=13.0, 3.3, 1H), 4.19 (t, J=7.1, 1H), 3.96 (d, J=5.2, 2H), 3.85 (dd, J=17.7, 8.7, 1H), 3.71 (dd, J=13.0, 9.0, 1H), 2.32 (m, 2H), 2.10 (m, 2H), 2.00 (dd, J=17.9, 7.9, 1H), 1.87-1.78 (m, 1H).

Example 311

Racemic 1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared using analogous conditions described in Example 51 utilizing 1H-benzo[d]imidazol-2(3H)-one. MS (ESI): mass calcd. for C₂₄H₂₄FN₅O₃, 449.19; m/z found, 450.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.29-8.24 (m, 1H), 7.99 (d, J=1.5, 1H), 7.50 (m, 1H), 7.23-7.13 (m, 2H), 7.06-6.93 (m, 3H), 6.63 (s, 2H), 5.36 (d, J=4.9, 1H), 4.18 (s, 1H), 4.00-3.91 (m, 3H), 3.89-3.78 (m, 2H), 2.32-2.20 (m, 2H), 2.14-2.01 (m, 2H), 1.99-1.89 (m, 1H), 1.79 (dd, J=18.7, 9.1, 1H).

Example 312

Racemic 1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}imidazolidin-2-one

The title compound was prepared using analogous conditions described in Example 51 utilizing imidazolidin-2-one. MS (ESI): mass calcd. for C₂₀H₂₄FN₅O₃, 401.19; m/z found, 402.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 7.21 (d, J=8.2, 1H), 6.64 (s, 2H), 6.31 (s, 1H), 5.20 (d, J=4.7, 1H), 3.94 (s, 1H), 3.87 (s, 3H), 3.25 (dd, J=19.6, 11.7, 5H), 3.09 (dd, J=13.8, 7.0, 1H), 2.30 (d, J=7.9, 2H), 2.15-2.05 (m, 2H), 2.00 (d, J=9.9, 1H), 1.82 (d, J=9.1, 1H).

Example 313

2′-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5,5′-bipyrimidin-2-amine Step A: 5-(3-((5-Bromopyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

To a microwave vial containing a stir-bar was added 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (100 mg, 0.386 mmol), 5-bromo-2-chloropyrimidine (74 mg, 0.39 mmol), cesium carbonate (188 mg, 0.580), and DMSO (2 mL). The vial was sealed and heated in the microwave for 30 minutes at 120° Celsius. The mixture was cooled to rt then passed through a syringe filter and the filtrate subjected to HPLC purification to give the title compound. ¹H NMR (500 MHz, 2 mL) δ 8.69 (d, J=1.5, 2H), 8.24 (s, 1H), 8.10 (s, 1H), 7.79-7.69 (m, 1H), 7.27 (d, J=8.3, 1H), 3.72-3.58 (m, 1H), 2.23-2.10 (m, 3H), 2.02-1.94 (m, 1H), 1.89-1.75 (m, 1H).

Step B: 2′-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5,5′-bipyrimidin-2-amine

5-(3-((5-Bromopyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine (60 mg, 0.14 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (32 mg, 0.14 mmol) were added to a sealable microwave vial equipped with a stir-bar. 1,4-Dioxane (0.58 mL) and Na₂CO₃ (2 M, 0.14 mL) were added And the mixture sparged with Ar for 10 min before adding Pd(dppf)Cl₂.CH₂Cl₂ (5 mg, 0.007 mmol) and heating the reaction mixture at 80° Celsius for 15 hours. The reaction was then cooled to rt, diluted with water (5 mL), and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C₂₂H₁₉FN₈O, 430.17; m/z found, 431.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.83 (s, 2H), 8.67 (s, 2H), 8.23 (s, 1H), 8.16 (s, 1H), 7.82-7.74 (m, 1H), 7.30 (d, J=8.3, 1H), 3.68 (p, J=8.9, 1H), 2.31-2.08 (m, 4H), 2.07-1.92 (m, 1H), 1.92-1.76 (m, 1H).

Intermediate J

3-(5-Aminopyrazin-2-yl)-2-fluoro-6-methylphenol Step A: tert-Butyl(2-fluoro-6-methylphenoxy)dimethylsilane

To a stirred solution of 2-fluoro-6-methylphenol (176 mg, 1.40 mmol) in DCM (6.3 mL), cooled to 0° Celsius, were added imidazole (142 mg, 2.09 mmol) followed by tert-butyldimethylsilyl chloride (231 mg, 1.54 mmol). The flask was warmed to rt and stirred for 2 hours The reaction mixture was then poured in to water (50 mL) and extracted with DCM (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness to provide the title compound that was used without further purification. ¹H NMR (500 MHz, CDCl₃) δ 6.91-6.85 (m, 2H), 6.80-6.73 (m, 1H), 2.24 (t, J=0.7, 3H), 1.02 (s, 9H), 0.20 (d, J=2.5, 6H).

Step B: (3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)boronic Acid

To a 25 mL flask vial were added a stir-bar, 2.1 mL dry THF, and 2,2,6,6-tetramethylpiperidine (0.22 mL, 1.0 mmol). The flask was cooled to −78° Celsius and then treated with n-BuLi (0.48 mL, 1.9 mmol, 2.5 M in hexanes) over 2 minutes. The resultant mixture was stirred for 5 min and then warmed to 0° Celsius. After 30 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)₃ (0.26 mL, 1.1 mmol) over 4 min. After 15 min, a solution consisting of tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane (247 mg, 1.03 mmol) in dry THF (2.1 mL) was added over the course of 6 min and stirring continued for 1 hour at −78° Celsius. The mixture was then warmed to rt, treated with HOAc (0.5 mL), and then poured into water (100 mL) and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (3×100 mL), the combined extracts dried over Na₂SO₄, filtered, and concentrated to dryness to give the title compound, which was used directly in the next synthetic step.

Step C: 5-(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)pyrazin-2-amine

(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)boronic acid (292 mg, 1.03 mmol), 2-amino-5-bromopyrazine (179 mg, 1.03 mmol), 1,4-dioxane (6.1 mL), and Na₂CO₃ (2.1 mL, 2 M) were added to a microwave vial and the resultant mixture sparged with argon for 10 minutes. Pd(dppf)Cl₂.DCM was then added the mixture, the vial sealed, and then heated at 80° Celsius for 16 hours. The reaction mixture was then cooled to rt, diluted with water (5 mL), and extracted with EtOAc (4×5 mL). The combined organic extracts were then dried over Na₂SO₄, filtered, and concentrated to dryness to provide the title compound. This compound was used directly in the next synthetic step without purification.

Step D: 3-(5-Aminopyrazin-2-yl)-2-fluoro-6-methylphenol

5-(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)pyrazin-2-amine (342 mg, 1.03 mmol) was dissolved in THF (1.2 mL) at rt and then treated with tetrabutylammonium fluoride (1.2 mL, 1 M in THF). The reaction was stirred for 1 hour at rt, before diluting with water (10 mL) and extracting with EtOAc (10 mL×4). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The crude product was purified by FCC to provide the title compound. ¹H NMR (500 MHz, CD₃OD) δ 8.26 (dd, J=2.3, 1.5, 1H), 8.01 (d, J=1.5, 1H), 7.09 (m, 1H), 6.94 (m, 1H), 2.25 (s, 3H).

Intermediate K

3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenol Step A: 2-Fluoro-6-vinylphenol

To a round-bottomed flask containing a stir-bar were added, methyltriphenylphosphonium bromide (5.6 g, 16 mmol) and anhydrous THF (50 mL). The mixture was stirred until homogeneous and then cooled to 0° Celsius. The flask was then charged drop-wise with n-BuLi (6.85 mL, 2.5 M in hexanes). The resultant solution was stirred for 30 minutes and then transferred via cannula to a stirred mixture of 3-fluoro-2-hydroxybenzaldehyde (1 g, 7 mmol) and THF (28 mL) at rt under an argon atmosphere. The resultant mixture was stirred for 3 h before quenching with saturated NH₄Cl (50 mL), diluting with water, and extracting with ether (3×100 mL). The combined ethereal extracts were dried over magnesium sulfate, filtered through a plug of silica gel, and then concentrated to dryness to provide the title compound that was used without further purification. ¹H NMR (500 MHz, CDCl₃) δ 7.20 (m, 1H), 7.04-6.92 (m, 2H), 6.80 (m, 1H), 5.81 (dd, J=17.8, 1.3, 1H), 5.69 (s, 1H), 5.35 (dd, J=11.2, 1.3, 1H).

Step B: tert-Butyl(2-fluoro-6-vinylphenoxy)dimethylsilane

The title compound was prepared in an analogous way to tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane in Step A of Intermediate J using 2-fluoro-6-vinylphenol. ¹H NMR (500 MHz, CDCl₃) δ 7.26 (m, 1H), 7.03 (dd, J=17.8, 11.1, 1H), 6.96 (m, 1H), 6.89-6.81 (m, 1H), 5.68 (dd, J=17.8, 1.3, 1H), 5.34-5.24 (m, 1H), 1.02 (s, 9H), 0.19 (d, J=2.4, 6H).

Step C: tert-Butyl(2-ethyl-6-fluorophenoxy)dimethylsilane

To a stirred solution of tert-butyl(2-fluoro-6-vinylphenoxy)dimethylsilane (1.18 g, 4.67 mmol) in ethyl acetate (61 mL) under nitrogen, was added 497 mg of 10% palladium on carbon. The flask was then equipped with a hydrogen containing balloon and the reaction mixture stirred rapidly for 4 hours. The hydrogen balloon was removed, the reaction mixture sparged with nitrogen, and then filtered through a plug of Celite®, eluting with EtOAc. The filtrate was concentrated to dryness to afford the title compound that was used without further purification. ¹H NMR (500 MHz, CDCl₃) δ 6.94-6.85 (m, 2H), 6.85-6.77 (m, 1H), 2.65 (q, J=7.6, 2H), 1.19 (t, J=7.5, 3H), 1.02 (s, 9H), 0.21 (d, J=2.7, 6H).

Step D: 3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenol

The title compound was prepared in an analogous way to 3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol in Steps B-D of Intermediate J using tert-butyl(2-ethyl-6-fluorophenoxy)dimethylsilane. ¹H NMR (500 MHz, CD₃OD) δ 8.26 (dd, J=2.3, 1.5, 1H), 8.02 (d, J=1.5, 1H), 7.12 (dd, J=8.0, 7.3, 1H), 6.99-6.93 (m, 1H), 2.68 (q, J=7.5, 2H), 1.21 (t, J=7.5, 3H).

Intermediate L

3-(5-Aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenol

The title compound was prepared using conditions similar to those described in Method 2 for 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol using cycloproplyzinc bromide in Step B. ¹H NMR (500 MHz, CD₃OD) δ 8.29-8.24 (m, 1H), 8.02 (d, J=1.5, 1H), 7.16-7.05 (m, 1H), 6.65 (dd, J=8.2, 1.3, 1H), 2.28-2.11 (m, 1H), 1.02-0.90 (m, 2H), 0.72-0.63 (m, 2H).

Intermediate M

3-(5-Aminopyrazin-2-yl)-2-fluoro-6-isopropylphenol

The title compound was prepared using conditions similar to those described in Method 2 for 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol using isoproplyzinc bromide in Step B. MS (ESI): mass calcd. for C₁₃H₁₄FN₃O, 247.11; m/z found, 248.1 [M+H]⁺.

Intermediate N

3-(5-Aminopyrazin-2-yl)-2-fluoro-6-propylphenol

The title compound was prepared using conditions similar to those described in Method 2 for 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol using proplyzinc bromide in Step B. MS (ESI): mass calcd. for C₁₃H₁₄FN₃O, 247.11; m/z found, 248.1 [M+H]⁺.

Example 314

5-[2-Fluoro-4-methyl-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloropyrimidine and 3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol. MS (ESI): mass calcd. for C₁₅H₁₂FN₅O, 297.10; m/z found, 298.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.22-8.20 (m, 1H), 8.20-8.19 (m, 1H), 7.73-7.68 (m, 1H), 7.27-7.24 (m, 1H), 7.22 (m, 1H), 2.23 (d, J=0.7, 3H).

Example 315

2-[3-(5-Aminopyrazin-2-yl)-2-fluoro-6-methylphenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloropyrimidin-4-amine and 3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol. MS (ESI): mass calcd. for C₁₅H₁₃FN₆O, 312.11; m/z found, 313.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.29-8.25 (m, 1H), 8.04 (d, J=1.5, 1H), 7.87 (d, J=5.9, 1H), 7.63-7.53 (m, 1H), 7.15 (d, J=8.1, 1H), 6.25 (d, J=5.9, 1H), 2.22 (s, 3H).

Example 316

5-[4-Ethyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloropyrimidine and 3-(5-aminopyrazin-2-yl)-6-ethyl-2-fluorophenol. MS (ESI): mass calcd. for C₁₆H₁₄FN₅O, 311.12; m/z found, 312.3 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.20 (dd, J=6.7, 1.6, 2H), 7.74 (dd, J=8.3, 7.5, 1H), 7.29-7.21 (m, 2H), 2.63 (q, J=7.6, 2H), 1.17 (t, J=7.6, 3H)

Example 317

2-[3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloropyrimidine-4-amine and 3-(5-aminopyrazin-2-yl)-6-ethyl-2-fluorophenol. MS (ESI): mass calcd. for C₁₆H₁₅FN₆O, 326.13; m/z found, 327.3 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.27 (m, 1H), 8.04 (d, J=1.5, 1H), 7.87 (d, J=5.9, 1H), 7.63 (m, 1H), 7.17 (dd, J=8.1, 1.3, 1H), 6.24 (d, J=5.9, 1H), 2.62 (q, J=7.6, 2H), 1.19 (t, J=7.6, 3H)

Example 318

5-[2-Fluoro-4-(1-methylethyl)-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloropyrimidine and 3-(5-aminopyrazin-2-yl)-2-fluoro-6-isopropylphenol. MS (ESI): mass calcd. for C₁₇H₁₆FN₅O, 325.13; m/z found, 326.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.62 (d, J=4.8, 2H), 8.25 (s, 1H), 8.04 (d, J=1.5, 1H), 7.72 (t, J=7.9, 1H), 7.28 (dd, J=8.4, 1.4, 1H), 7.25 (m, 1H), 3.18-3.10 (m, 1H), 1.22 (d, J=6.9, 6H).

Example 319

5-[2-Fluoro-4-propyl-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 heating at 120° Celsius via microwave irradiation for 1 hour and using 2-chloropyrimidine and 3-(5-aminopyrazin-2-yl)-2-fluoro-6-propylphenol. MS (ESI): mass calcd. for C₁₇H₁₆FN₅O, 325.13; m/z found, 326.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.25 (s, 1H), 8.04 (d, J=1.5, 1H), 7.71-7.62 (m, 1H), 7.27-7.23 (m, 1H), 7.20 (dd, J=8.2, 1.4, 1H), 2.58 (t, J=7.6, 2H), 1.66-1.51 (m, 2H), 0.90 (t, J=7.3, 3H).

Example 320

5-(4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine Step A: tert-Butyl(2-cyclohexyl-6-fluorophenoxy)dimethylsilane

A solution consisting of (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (0.832 g, 2.73 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.070 g, 0.14 mmol) and dry THF (5 mL) was treated with cyclohexylzinc(II) bromide (7.0 mL, 3.5 mmol, 0.5 M in THF). The resultant mixture was heated for 45 minutes at 50° C., cooled to rt, and concentrated to dryness. The resultant residue was subjected to FCC purification to the title compound (0.841 g, 89%) which was used without purification.

Step B: (3-((tert-Butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)boronic Acid

A solution consisting of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) and dry THF (2 mL) was cooled to −78° C. and treated with n-butyllithium (1.1 mL, 2.75 mmol, 2.5 M in hexanes). After stirring for 5 minutes, the reaction was warmed to rt for 5 minutes before cooling back down to −78° C. The reaction was then treated with tert-butyl(2-cyclohexyl-6-fluorophenoxy)dimethylsilane (0.719 g, 2.33 mmol) and triisopropyl borate (0.60 mL, 2.6 mmol) and stirred for 5 minutes. The reaction mixture was warmed to rt, quenched with saturated NH₄Cl (2 mL), and extracted with EtOAc (2×5 mL). The combined organic extracts were washed with brine (3×5 mL), dried over MgSO₄, filtered, and concentrated to dryness to yield the title compound (0.833 g, 101%), which was used without purification.

Step C: 5-(3-((tert-Butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)pyrazin-2-amine

A mixture of (3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)boronic acid (0.821 g, 2.33 mmol), 5-bromopyrazin-2-amine (0.40 g, 2.3 mmol), K₂CO₃ (0.659 g, 4.77 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.086 g, 0.12 mmol), deoxygenated toluene (10 mL), and deoxygenated deionized water (10 mL) was heated for 16 hours at 80° Celsius. The reaction mixture was then cooled to rt, diluted with dichloromethane (25 mL), and washed with brine (2×25 mL). The organic layer was dried over MgSO₄, filtered, and concentrated to dryness to yield the title compound (0.936 g, 100%) which was used without purification.

Step D: 3-(5-Aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol

A solution consisting of 5-(3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)pyrazin-2-amine (936 mg, 2.33 mmol) and THF (15 mL) was treated with tetrabutylammonium fluoride (5 mL, 5 mmol, 1 M in THF). The reaction mixture was stirred for 16 hours at which point it was concentrated to dryness and purified by FCC to yield the title compound (0.403 g, 60%) which was used without further purification. MS (ESI): mass calcd. for C₁₆H₁₈FN₃O, 287.14; m/z found, 288.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47-8.45 (m, 1H), 8.09 (d, J=1.5, 1H), 7.32 (m, 1H), 7.06-7.03 (m, 1H), 5.60 (d, J=6.3, 1H), 4.65 (s, 2H), 3.00-2.92 (m, 1H), 1.94-1.81 (m, 4H), 1.80-1.74 (m, 1H), 1.52-1.38 (m, 4H), 1.33-1.25 (m, 1H).

Step E: 5-(4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

A mixture consisting of 3-(5-aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol (0.05 g, 0.2 mmol), 2-chloropyrimidine (0.025 g, 0.22 mmol), K₂CO₃ (0.05 g, 0.4 mmol), and 18-crown-6 (0.01 g, 0.04 mmol), and DMSO (2 mL) was heated via microwave irradiation for 1 hour at 120° Celsius. After cooling to room temperature, the reaction mixture was filtered and purified directly via HPLC to yield the title compound (42 mg, 65%). MS (ESI): mass calcd. for C₂₀H₂₀FN₅O, 365.17; m/z found, 366.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.63-8.60 (m, 2H), 8.28-8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.80-7.76 (m, 1H), 7.31-7.23 (m, 2H), 2.81-2.74 (m, 1H), 1.83-1.68 (m, 5H), 1.53-1.43 (m, 2H), 1.35-1.24 (m, 3H).

Example 321

5-(4-(Cyclohexylmethyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to that described in Example 320 using (cyclohexylmethyl)zinc(II) bromide in Step A. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O, 379.18; m/z found, 380.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.26 (d, J=1.5, 1H), 8.21-8.19 (m, 1H), 7.75-7.71 (m, 1H), 7.27-7.24 (m, 1H), 7.20-7.15 (m, 1H), 2.49 (d, J=7.1, 2H), 1.68-1.60 (m, 5H), 1.55-1.47 (m, 1H), 1.17-1.09 (m, 3H), 0.98-0.88 (m, 2H).

Example 322

5-(2-Fluoro-4-isopentyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to that described in Example 320 using isopentylzinc(II) bromide in Step A. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.65-8.59 (m, 2H), 8.28-8.26 (m, 1H), 8.21-8.19 (m, 1H), 7.77-7.73 (m, 1H), 7.29-7.20 (m, 2H), 2.65-2.57 (m, 2H), 1.56-1.48 (m, 1H), 1.46-1.39 (m, 2H), 0.85 (s, 3H), 0.83 (s, 3H).

Example 323

5-(2-Fluoro-4-isobutyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to that described in Example 320 using isobutylzinc(II) bromide in Step A. MS (ESI): mass calcd. for C₁₈H₁₈FN₅O, 339.15; m/z found, 340.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.27 (d, J=1.4, 1H), 8.20 (m, 1H), 7.75 (t, J=7.8, 1H), 7.25 (m, 1H), 7.22-7.19 (m, 1H), 2.49 (d, J=7.3, 2H), 1.91-1.84 (m, 1H), 0.88 (d, J=6.6, 6H).

Example 324

5-(2-Fluoro-4-neopentyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to that described in Example 320 using neopentylzinc(II) bromide in Step A. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.26-8.25 (m, 1H), 8.21 (s, 1H), 7.74 (t, J=7.9, 1H), 7.24 (m, 1H), 7.22-7.19 (m, 1H), 2.53 (s, 2H), 0.94 (s, 9H).

Example 325

2-(3-(5-Aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenoxy)pyrimidin-4-amine

The title compound was prepared in a manner analogous to that described in Example 320 using 2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.26-8.25 (m, 1H), 8.13 (d, J=1.5, 1H), 8.06 (d, J=7.0, 1H), 7.80 (m, 1H), 7.32-7.29 (m, 1H), 6.51 (d, J=7.0, 1H), 2.79-2.71 (m, 1H), 1.89-1.80 (m, 4H), 1.78-1.73 (m, 1H), 1.56-1.47 (m, 2H), 1.44-1.26 (m, 3H).

Example 326

2-(3-(5-Aminopyrazin-2-yl)-6-(cyclohexylmethyl)-2-fluorophenoxy)pyrimidin-4-amine

The title compound was prepared in a manner analogous to that described in Example 320 using (cyclohexylmethyl)zinc(II) bromide in Step A and 2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. for C₂₁H₂₃FN₆O, 394.19; m/z found, 395.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.28-8.26 (m, 1H), 8.11 (d, J=1.5, 1H), 8.05 (d, J=7.0, 1H), 7.76 (t, J=7.9, 1H), 7.22-7.19 (m, 1H), 6.51 (d, J=7.1, 1H), 2.53 (d, J=7.2, 2H), 1.73-1.65 (m, 5H), 1.60-1.52 (m, 1H), 1.23-1.14 (m, 3H), 1.04-0.94 (m, 2H).

Example 327

2-(3-(5-Aminopyrazin-2-yl)-2-fluoro-6-isopentylphenoxy)pyrimidin-4-amine

The title compound was prepared in a manner analogous to that described in Example 320 using isopentylzinc(II) bromide in Step A and 2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. for C₁₉H₂₁FN₆O, 368.18; m/z found, 369.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.27-8.26 (m, 1H), 8.11 (d, J=1.5, 1H), 8.05 (d, J=7.0, 1H), 7.77 (t, J=7.9, 1H), 7.26-7.23 (m, 1H), 6.51 (d, J=7.0, 1H), 2.68-2.62 (m, 2H), 1.62-1.54 (m, 1H), 1.52-1.46 (m, 2H), 0.91 (d, J=6.5, 6H).

Example 328

2-(3-(5-Aminopyrazin-2-yl)-2-fluoro-6-isobutylphenoxy)pyrimidin-4-amine

The title compound was prepared in a manner analogous to that described in Example 320 using isobutylzinc(II) bromide in Step A and 2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. for C₁₈H₁₉FN₆O, 354.16; m/z found, 355.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.28-8.26 (m, 1H), 8.12 (d, J=1.5, 1H), 8.05 (d, J=7.0, 1H), 7.77 (t, J=7.9, 1H), 7.24-7.21 (m, 1H), 6.50 (d, J=7.0, 1H), 2.53 (d, J=7.3, 2H), 1.97-1.87 (m, 1H), 0.94 (d, J=6.6, 6H).

Example 329

5-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidine-2-carboxamide

The title compound was prepared using analogous conditions to those described in Example 69 utilizing 5-bromo-2-cyanopyrimidine. MS (ESI): mass calcd. for C₁₉H₁₇FN₆O, 380.14; m/z found, 381.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.56 (s, 2H), 8.27 (s, 1H), 8.10 (d, J=1.5, 1H), 7.88-7.81 (m, 1H), 7.40 (d, J=8.2, 1H), 3.76-3.64 (m, 1H), 2.33-2.14 (m, 5H), 2.10-1.97 (m, 1H), 1.93-1.80 (m, 1H).

Example 330

5-(4-Cyclobutyl-2-fluoro-3-(thiazolo[4,5-b]pyridin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions to those described in Example 69 utilizing 2-chlorothiazolo[4,5-b]pyridine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 393.11; m/z found, 394.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (dd, J=4.8, 1.7, 1H), 8.45 (dd, J=8.0, 1.7, 1H), 8.33-8.28 (m, 1H), 8.03 (d, J=1.5, 1H), 7.91-7.83 (m, 1H), 7.42-7.34 (m, 2H), 6.72 (br s, 2H), 3.67 (p, J=8.9, 1H), 2.27-2.09 (m, 4H), 2.03-1.89 (m, 1H), 1.84-1.73 (m, 1H).

Example 331

5-(4-Cyclobutyl-2-fluoro-3-((5-methylthieno[2,3-d]pyrimidin-4-yl)oxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions to those described in Example 69 utilizing 4-chloro-5-methylthieno[2,3-d]pyrimidine. MS (ESI): mass calcd. for C₂₁H₁₈FN₅OS, 407.12; m/z found, 408.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.29-8.25 (m, 1H), 8.01 (d, J=1.5, 1H), 7.82-7.76 (m, 1H), 7.61 (d, J=1.4, 1H), 7.32 (d, J=8.3, 1H), 6.70 (s, 2H), 3.63-3.53 (m, 1H), 2.66 (d, J=1.3, 3H), 2.31-2.22 (m, 1H), 2.22-2.12 (m, 1H), 2.10-2.01 (m, 1H), 2.01-1.95 (m, 1H), 1.94-1.84 (m, 1H), 1.78-1.69 (m, 1H).

Example 332

N⁴-(2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)ethyl)pyrimidine-2,4-diamine

The title compound was prepared using analogous conditions described in Example 295 utilizing 2-amino-4-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₂₂FN₇O, 395.19; m/z found, 396.2 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.30-8.24 (m, 1H), 8.03 (d, J=1.5, 1H), 7.64 (br s, 1H), 7.50-7.43 (m, 1H), 7.19 (d, J=8.2, 1H), 5.93 (d, J=6.1, 1H), 4.14 (t, J=5.4, 2H), 3.83 (m, 1H), 3.78-3.67 (m, 2H), 2.31-2.21 (m, 2H), 2.17-2.06 (m, 2H), 2.05-1.93 (m, 1H), 1.87-1.78 (m, 1H).

Example 333

3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenol

The title compound was prepared in a manner analogous to that described for Intermediate K. MS (ESI): mass calcd. for C₁₂H₁₂FN₃O, 233.10; m/z found, 234.1 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.26 (dd, J=2.3, 1.5 Hz, 1H), 8.02 (d, J=1.5 Hz, 1H), 7.12 (dd, J=8.0, 7.3 Hz, 1H), 6.99-6.93 (m, 1H), 2.68 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H)

Example 334

5-[4-Cyclopentyl-2-fluoro-3-pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

The title compound was prepared in a manner analogous to that described in Example 320 using cyclopentylzinc(II) bromide in Step A and 5-bromopyrimidin-2-amine in Step C. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (d, J=4.8 Hz, 2H), 8.55 (d, J=1.2 Hz, 2H), 7.41-7.35 (m, 1H), 7.34-7.28 (m, 1H), 7.25 (t, J=4.8 Hz, 1H), 3.25-3.15 (m, 1H), 2.00-1.88 (m, 2H), 1.87-1.73 (m, 2H), 1.71-1.53 (m, 4H).

Example 335

5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclopentyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared in a manner analogous to that described in Example 320 using cyclopentylzinc(II) bromide in Step A, 5-bromopyrimidin-2-amine in Step C and 2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. for C₁₉H₁₉FN₆O, 366.16; m/z found, 367.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.45 (d, J=1.2 Hz, 2H), 7.87 (d, J=5.9 Hz, 1H), 7.31-7.27 (m, 1H), 7.26-7.21 (m, 1H), 6.25 (d, J=5.9 Hz, 1H), 3.26-3.10 (m, 1H), 2.04-1.91 (m, 2H), 1.85-1.74 (m, 2H), 1.70-1.55 (m, 4H).

Example 336

2-[3-(5-Aminopyrazin-2-yl)-6-cyclopentyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared in a manner analogous to that described in Example 320 using cyclopentylzinc(II) bromide in Step A and 2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. for C₁₉H₁₉FN₆O, 366.16; m/z found, 367.2 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.35-8.21 (m, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.87 (d, J=5.9 Hz, 1H), 7.71-7.57 (m, 1H), 7.30-7.17 (m, 1H), 6.24 (d, J=5.9 Hz, 1H), 3.23-3.12 (m, 1H), 2.03-1.89 (m, 2H), 1.88-1.74 (m, 2H), 1.72-1.52 (m, 4H).

Example 337

5-[4-Cyclopentyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared in a manner analogous to that described in Example 320 using cyclopentylzinc(II) bromide in Step A. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (d, J=4.8 Hz, 2H), 8.24-8.21 (m, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.75-7.70 (m, 1H), 7.29 (dd, J=8.5, 1.4 Hz, 1H), 7.26-7.22 (m, 1H), 3.25-3.10 (m, 1H), 2.01-1.88 (m, 2H), 1.87-1.70 (m, 2H), 1.70-1.56 (m, 4H).

Example 338

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-3-amine

The title compound was prepared in a manner analogous to that described in Example 160 using 6-fluoropyridazin-3-amine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.26 (dd, J=2.3, 1.4 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.72-7.61 (m, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.22 (d, J=9.4 Hz, 1H), 7.08 (d, J=9.4 Hz, 1H), 3.66 (p, J=9.0 Hz, 1H), 2.27-2.09 (m, 4H), 2.05-1.93 (m, 1H), 1.87-1.77 (m, 1H).

Example 339

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 243 using 2-(chloromethyl)pyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.84 (d, J=5.0 Hz, 2H), 8.27 (dd, J=2.4, 1.5 Hz, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.52 (dd, J=8.2, 7.4 Hz, 1H), 7.48 (t, J=5.0 Hz, 1H), 7.24-7.17 (m, 1H), 5.24 (s, 2H), 4.00-3.85 (m, 1H), 2.33-2.21 (m, 2H), 2.21-2.08 (m, 2H), 2.08-1.94 (m, 1H), 1.92-1.77 (m, 1H).

Example 340

5-{3-[(4-Bromobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using analogous conditions described in Example 243 using 1-bromo-4-(bromomethyl)benzene. MS (ESI): mass calcd. for C₂₁H₁₉BrFN₃O, 427.07; m/z found, 428.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (dd, J=2.3, 1.5 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.57-7.52 (m, 2H), 7.52-7.46 (m, 1H), 7.43-7.35 (m, 2H), 7.23-7.13 (m, 1H), 5.02 (s, 2H), 3.76 (p, J=8.8 Hz, 1H), 2.32-2.20 (m, 2H), 2.20-2.07 (m, 2H), 2.07-1.96 (m, 1H), 1.91-1.77 (m, 1H).

Example 341

5-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)pyrimidin-2-amine

To a sealable vial were added 5-{3-[(4-bromobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine (42 mg, 0.098 mmol) and (2-aminopyrimidin-5-yl)boronic acid (13 mg, 0.098 mmol), followed by 1,4-dioxane (0.5 mL) and Na₂CO₃ (0.2 mL, 2 M). The mixture was sparged with argon for 10 minutes then Pd(dppf)Cl₂.CH₂Cl₂ (4 mg, 0.005 mmol) was added and the vial was sealed. The vial was heated at 80° C. for 3 hours before cooling it to RT and partitioning its contents between EtOAc (50 mL) and water (50 mL). The aqueous layer was washed with EtOAc (50 mL) and the combined organic extracts were dried with Na₂SO₄, filtered and concentrated to dryness. The resultant residue was purified by prep-HPLC to provide the title compound. MS (ESI): mass calcd. for C₂₅H₂₃FN₆O, 442.19; m/z found, 443.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 2H), 8.30-8.27 (m, 1H), 8.10 (d, J=1.5 Hz, 1H), 7.67-7.62 (m, 2H), 7.62-7.57 (m, 2H), 7.56-7.49 (m, 1H), 7.20 (d, J=8.3 Hz, 1H), 5.11 (s, 2H), 3.81 (t, J=8.9 Hz, 1H), 2.34-2.22 (m, 2H), 2.21-2.08 (m, 2H), 2.01 (q, J=10.0 Hz, 1H), 1.92-1.80 (m, 1H).

Example 342

5-(4-Cyclobutyl-2-fluoro-3-{[4′-trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pyrazin-2-amine

The title compound was prepared in an analogous manner to Example 341 using (4-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. for C₂₈H₂₃F₄N₃O, 493.18; m/z found, 494.1 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 8.32-8.28 (m, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.88-7.81 (m, 2H), 7.78-7.70 (m, 4H), 7.62-7.57 (m, 2H), 7.51 (dd, J=8.2, 7.4 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 5.12 (s, 2H), 3.93-3.74 (m, 1H), 2.35-2.22 (m, 2H), 2.22-2.09 (m, 2H), 2.08-1.94 (m, 1H), 1.90-1.79 (m, 1H).

Example 343

5-[4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine Step A: 1-bromo-3-fluoro-2-(methoxymethoxy)benzene

To a solution consisting of 2-bromo-6-fluorophenol (5.0 g, 26 mmol), DIPEA (9.0 mL, 52.4 mmol) and CH₂Cl₂ (131 mL) was added chloro(methoxy)methane (2.2 mL, 29 mmol). The reaction mixture was stirred at RT for 1 h, then washed with sat. aq. NaHCO₃ (30 mL). The organic layer was isolated, concentrated to dryness and the resultant residue was purified by FCC to afford the title compound (5.5 g, 89%). ¹H NMR (500 MHz, CDCl₃) δ 7.36-7.31 (m, 1H), 7.10-7.03 (m, 1H), 6.97-6.92 (m, 1H), 5.20 (s, 2H), 3.65 (s, 3H).

Step B: 1-Cyclohexyl-3-fluoro-2-(methoxymethoxy)benzene

To a round-bottomed flask, were added a stir bar, 1-bromo-3-fluoro-2-(methoxymethoxy)benzene (12.9 g, 12.3 mmol) and THF (41 mL). The flask was sealed with a rubber septa and flushed with N₂ for 5 minutes. Bis(tri-tert-butylphosphine)palladium(0) (473 mg, 0.92 mmol) was then added to the flask, followed by cyclohexylzinc(II) bromide (0.5 M in THF, 37 mL, 19 mmol). The reaction mixture was heated at 60° C. for 1 h, cooled to RT, concentrated onto silica gel and purified by FCC to afford the title compound (2.4 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 7.02-6.96 (m, 2H), 6.96-6.86 (m, 1H), 5.11 (s, 2H), 3.61 (s, 3H), 3.07-2.97 (m, 1H), 1.89-1.77 (m, 4H), 1.46-1.21 (m, 6H).

Step C: (4-Cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)boronic Acid

To a solution of 2,2,6,6-tetramethylpiperidine (3.2 mL, 19 mmol) and THF (40 mL), at −78° C., was added n-butyllithium (2.3 M in hexanes, 8.2 mL, 19 mmol) drop-wise. The reaction mixture was allowed to warm to 0° C., stirred 5 min, and cooled to −78° C. Triisopropyl borate (4.3 mL, 19 mmol) was added, followed by a solution consisting of 1-cyclohexyl-3-fluoro-2-(methoxymethoxy)benzene (3.0 g, 13 mmol) and THF (20 mL). The mixture was stirred for 5 min at −78° C., warmed to RT, and quenched with sat. NH₄Cl (20 mL). The mixture was partitioned between water (20 mL) and EtOAc (40 mL). The organic phases were separated and the aqueous solution was further extracted with EtOAc (2×40 mL). The organic extracts were combined, concentrated to dryness and the crude product was used directly.

Step D: 5-(4-Cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)pyrimidin-2-amine

A solution consisting of (4-cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)boronic acid (1.4 g, 5.0 mmol), 2-amino-5-bromopyrimidine (0.95 g, 5.5 mmol) and THF (25 mL) was sparged with N₂ for 10 min. A solution of Na₂CO₃ (25 mL, 50 mmol, 2 M) was then added and the mixture was further sparged with N₂ for 20 min. 1,1″bis(di-t-butylphosphino)ferrocene palladium dichloride (162 mg, 0.25 mmol) was added, the reaction mixture was heated at 50° C. for 2 h, cooled to RT and diluted with EtOAc (50 mL). The organic phase was isolated, concentrated onto silica, and purified by FCC to provide the title compound (0.84 g, 51%). MS (ESI): mass calcd. for C₁₈H₂₂FN₃O₂, 331.17; m/z found, 332.3 [M+H]⁺.

Step E: 3-(2-Aminopyrimidin-5-yl)-6-cyclohexyl-2-fluorophenol

To a solution consisting of 5-(4-cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)pyrimidin-2-amine (840 mg, 2.5 mmol) and CH₂Cl₂ (25 mL), was added TFA (0.6 mL, 7.6 mmol), and the reaction mixture was stirred at RT for 12 h. The reaction mixture was then diluted with CH₂Cl₂ (95 mL) and washed with sat. aq. NaHCO₃ (50 mL). The organic layer was isolated, concentrated to dryness, and the resulting residue was purified by FCC to afford the title compound.

Step F: 5-[4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

To a microwave vial equipped with a stir-bar, were added 3-(2-aminopyrimidin-5-yl)-6-cyclohexyl-2-fluorophenol (100 mg, 0.35 mmol), 2-chloropyrimidine (42 mg, 0.35 mmol), K₂CO₃ (96 mg, 0.70 mmol), 18-crown-6 (5 mg, 0.02 mmol) and DMA (0.5 mL). The vial was capped and irradiated in a microwave reactor for 10 min at 110° C., before cooling to RT and diluting with EtOAc (10 mL) and water (5 mL). The organic layer was isolated, concentrated to dryness and the resultant residue was purified by prep-HPLC to provide the title compound (65 mg, 39%). MS (ESI): mass calcd. for C₂₀H₂₀FN₅O 365.17; m/z found, 366.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.62 (d, J=4.8 Hz, 2H), 8.56 (d, J=1.2 Hz, 2H), 7.44-7.36 (m, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 7.26 (t, J=4.8 Hz, 1H), 2.85-2.70 (m, 1H), 1.86-1.64 (m, 5H), 1.59-1.39 (m, 2H), 1.35-1.21 (m, 3H).

Example 344

5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclohexyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using analogous conditions to those described in Example 343 using 4-amino-2-chloropyrimidine in step F. MS (ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.44 (d, J=1.4 Hz, 2H), 7.87 (d, J=6.0 Hz, 1H), 7.34-7.26 (m, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.25 (d, J=6.0 Hz, 1H), 2.84-2.68 (m, 1H), 1.87-1.65 (m, 5H), 1.52-1.20 (m, 5H).

Example 345

3-(5-Aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol

The title compound was prepared in a manner analogous to that described in Steps A-D for Example 320 using cyclohexylzinc(II) bromide in Step A. MS (ESI): mass calcd. for C₁₆H₁₈FN₃O, 287.14; m/z found, 288.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47-8.45 (m, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.36-7.29 (m, 1H), 7.06-7.03 (m, 1H), 5.60 (d, J=6.3 Hz, 1H), 4.65 (s, 2H), 3.00-2.92 (m, 1H), 1.94-1.81 (m, 4H), 1.80-1.74 (m, 1H), 1.52-1.38 (m, 4H), 1.33-1.25 (m, 1H).

Example 346

3-(5-Aminopyrazin-2-yl)-6-(cyclohexylmethyl)-2-fluorophenol

The title compound was prepared in a manner analogous to that described in Steps A-D for Example 320 using (cyclohexylmethyl)zinc(II) bromide in Step A. ¹H NMR (500 MHz, CDCl₃) δ 8.47-8.45 (m, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.30-7.26 (m, 1H), 6.95-6.93 (m, 1H), 5.62 (s, 1H), 4.66 (s, 2H), 2.56 (d, J=7.1 Hz, 2H), 1.74-1.58 (m, 7H), 1.23-1.13 (m, 3H), 1.05-0.94 (m, 2H).

Example 347

5-{3-[(2-Aminopyridin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 164 using 2-amino-4-bromopyridine with DMSO as the solvent, heating via microwave irradiation at 140° C. for 10 hours. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.46 (m, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.93 (d, J=5.9 Hz, 1H), 7.83-7.76 (m, 1H), 7.24 (d, J=8.3 Hz, 1H), 6.30-6.24 (m, 1H), 5.89 (d, J=2.2 Hz, 1H), 4.71 (s, 2H), 4.40 (s, 2H), 3.64-3.53 (m, 1H), 2.29-2.07 (m, 4H), 2.03-1.90 (m, 1H), 1.87-1.76 (m, 1H).

Example 348

5-{3-[(6-Aminopyrazin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 164 using 2-amino-6-chloropyrazine with DMSO as the solvent, heating via microwave irradiation at 140° C. for 6 hours. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.24 (m, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.72-7.65 (m, 1H), 7.55 (d, J=3.8 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 6.70 (s, 2H), 6.51 (s, 2H), 3.60-3.47 (m, 1H), 2.22-2.03 (m, 4H), 1.99-1.85 (m, 1H), 1.83-1.70 (m, 1H).

Example 349

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-5-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 164 using 5-bromopyrimidine with DMSO as the solvent, heating via microwave irradiation at 140° C. for 2 hours. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13; m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.46-8.42 (m, 1H), 8.40 (s, 2H), 8.09 (d, J=1.5 Hz, 1H), 7.87-7.80 (m, 1H), 7.31-7.27 (m, 1H), 4.78 (s, 2H), 3.69-3.58 (m, 1H), 2.30-2.10 (m, 4H), 2.07-1.92 (m, 1H), 1.90-1.76 (m, 1H).

Example 350

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-4-amine

The title compound was prepared using conditions similar to those described in Example 164 using 6-chloro-4-pyridazinamine with DMSO as the solvent, heating via microwave irradiation at 180° C. for 2 hours. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (d, J=2.0 Hz, 1H), 8.25 (s, 1H), 8.04-7.97 (m, 1H), 7.74-7.67 (m, 1H), 7.26 (d, J=8.3 Hz, 1H), 6.68 (s, 2H), 6.60 (s, 2H), 6.23 (d, J=2.0 Hz, 1H), 3.58-3.46 (m, 1H), 2.17-2.02 (m, 4H), 1.98-1.84 (m, 1H), 1.80-1.69 (m, 1H).

Example 351

5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine Step A: (3-bromo-6-(tert-butyl)-2-fluorophenoxy)(tert-butyl)dimethylsilane

To a 100 mL round-bottomed flask were added a stir-bar, THF (38.0 mL), tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (5.0 g, 18 mmol), and N,N,N′,N′-tetramethylethylenediamine (1.6 mL, 19 mmol). The flask was cooled to −78° C. and then treated with sec-BuLi (14 mL, 20 mmol, 1.4 M in hexanes) over 6 min. The resulting mixture was stirred for 2 hr, before treating it with a solution consisting of carbon tetrabromide (8.7 mL, 26 mmol) and THF (8.0 mL) over the course of 2 min. The resulting mixture was stirred for an additional 2 h at −78° C. The reaction mixture was then warmed to RT and stirred another 18 h. The reaction mixture was then poured into sat. aq NH₄Cl and extracted with EtOAc (200 mL). The organic phase was isolated, dried over Na₂SO₄, filtered and concentrated to dryness. Purification by FCC yielded the title compound.

Step B: 3-Bromo-6-(tert-butyl)-2-fluorophenol

To a 100 mL round-bottomed flask were added a stir-bar, (3-bromo-6-(tert-butyl)-2-fluorophenoxy)(tert-butyl)dimethylsilane (6.4 g, 18 mmol), THF (44.0 mL) and TBAF (25.0 g, 24.0 mmol, 1M in THF). The mixture was stirred for 2 hr and then poured into NH₄Cl (100 mL, sat. aq.). The aqueous mixture was then extracted with EtOAc (200 mL), the organic extract was dried over Na₂SO₄, filtered and concentrated to dryness. Purification by FCC yielded the title compound.

Step C: 2-(3-Bromo-6-(tert-butyl)-2-fluorophenoxy)pyrimidine

To a 20 mL microwave vial were added a stir-bar, 3-bromo-6-(tert-butyl)-2-fluorophenol (1.4 g, 5.7 mmol), 2-chloropyrimidine (0.76 g, 6.3 mmol), cesium carbonate (3.6 g, 11 mmol), and acetonitrile (11.0 mL). The mixture was heated at 80° C. for 18 hr. The reaction mixture was filtered and the filtrate was directly subjected to FCC to provide the title compound (0.95 g, 51%)¹H NMR (400 MHz, CDCl₃) 8.58 (d, J=4.8 Hz, 2H), 7.37 (dd, J=8.8, 6.7 Hz, 1H), 7.12 (dd, J=8.8, 1.9 Hz, 1H), 7.09-7.05 (m, 1H), 1.35 (s, 9H).

Step D: 5-4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl-1H-pyrrolo[2,3-b]pyridine

5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine was coupled to 2-(3-bromo-6-(tert-butyl)-2-fluorophenoxy)pyrimidine in an analogous manner to Step D in Intermediate A to give the title compound (10 mg, 8%). MS (ESI): mass calcd. for C₂₁H₁₉FN₄O, 362.15; m/z found, 363.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.11 (s, 1H), 8.60 (d, J=4.8 Hz, 2H), 8.53-8.46 (m, 1H), 8.15-8.08 (m, 1H), 7.40-7.30 (m, 3H), 7.11-7.01 (m, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 1.45-1.41 (m, 9H).

The following Examples 1-36 summarized in Table 4 are prophetic and unless otherwise specified, can be readily synthesized by a person skilled in the art utilizing the above described reaction schemes or by synthesis routes generally known to a person skilled in the art. One skilled in the art based on presently disclosed compounds would conclude the following prophetic compounds to be active against FLAP.

TABLE 4 Prophetic Examples STRUCTURE No. NAME

1 5-(2-fluoro-4-(pentan-3-yl)-3-(pyrimidin- 2-yloxy)phenyl)pyrazin-2-amine

2 5-(fluoro-4-methyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

3 5-(4-ethyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

4 5-(2-fluoro-4-propyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

5 5-(2-fluoro-4-isopropyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

6 5-(4-cyclopropyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)pyrimidn-2-amine

7 5-(2-fluoro-4-isobutyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

8 5-(2-fluoro-4-neopentyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

9 5-(2-fluoro-4-(pentan-3-yl)-3-(pyrimidin- 2-yloxy)phenyl)pyrimidin-2-amine

10 5-(4-cyclohexyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

11 5-(4-(cyclohexylmethyl)-2-fluoro-3- (pyrimidin-2-yloxy)phenyl)pyrimidin-2- amine

12 5-(2-fluoro-4-isopentyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

13 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-4-methylpyrimidin-2- amine

14 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-4-methylpyrimidin-2- amine

15 3-chloro-5-(4-cyclobutyl-2- fluoro-3-(pyrimidin-2- yloxy)phenyl)pyridin-2-amine

16 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-chloropyridin-2-amine

17 2-amino-5-(4-cyclobutyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl)nicotinonitrile

18 2-amino-5-(4-(tert-butyl)-2- fluoro-3-(pyrimidin-2- yloxy)phenyl)nicotinonitrile

19 5-(4-cyclobutyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl)-3- fluoropyridin-2-amine

20 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-fluoropyridin-2-amine

21 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-(trifluoromethyl)pyridin- 2-amine

22 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-(trifluoromethyl)pyridin- 2-amine

23 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)pyridine-2,3-diamine

24 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)pyridine-2,3-diamine

25 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-methylpyrazin-2-amine

26 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-methylpyrazin-2-amine

27 3-chloro-5-(4-cyclobutyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl)pyrazin-2- amine

28 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-chloropyrazin-2-amine

29 3-amino-6-(4-cyclobutyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl)pyrazine-2- carbonitrile

30 3-amino-6-(4-(tert-butyl)-2-fluoro-3- (pyrimidin-2-yloxy)phenyl)pyrazine-2- carbonitrile

31 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-fluoropyrazin-2-amine

32 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-fluoropyrazin-2-amine

33 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-methoxypyrazin-2- amine

34 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)-3-methoxypyrazin-2- amine

35 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)pyrazine-2,3-diamine

36 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)pyrazine-2,3-diamine

D) General Administration, Formulation, and Dosages

The present invention provides substituted heteroaryl ketone compounds which are useful as FLAP modulators.

The invention features a method for treating a subject in need thereof with an FLAP-mediated disease and/or disorder, said method comprising administering to the subject a therapeutically effective amount of a compound of the invention. In particular, the invention also provides a method for treating or inhibiting the progression of an FLAP-mediated disease and/or disorder, or associated symptoms or complications thereof in a subject afflicted with such a disease and/or disorder, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.

Embodiments of the present invention include a method wherein the compound of Formula (I) is a FLAP modulator.

Embodiments of the present invention include a use of the compound of Formula (I) in the manufacture of a medicament for treating an FLAP-mediated disease and/or disorder.

Embodiments of the present invention include a use of the compound of Formula (I) as a medicine.

The compounds of Formula (I) have an FLAP-modulating effect and are useful as therapeutic agents for various FLAP-mediated disorders and/or disorders, or associated symptoms or complications, for example, respiratory disorders, cardiac and cardiovascular diseases, autoimmune disorders, carcinogenesis, and associated symptoms or complications thereof.

The compounds of Formula (I) may be administered orally or parenterally, and after formulation into preparations suitable for the intended administration route, they can be used as therapeutic agents for treating an FLAP-mediated disease and/or disorder. FLAP-mediated diseases and/or disorders include, but are not limited, diseases and/or disorders that are related to leukotriene synthesis pathway, and therefore may be treated, controlled or in some cases prevented, by treatment with the compounds of this invention.

One aspect of the present invention provides a method for the treatment of diseases and/or disorders, or associated symptoms or complications thereof, responsive to the modulation of FLAP in a subject in need thereof which comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula (I) or a form thereof.

Another aspect of the present invention provides a method for the treatment of a disease and/or disorder selected from the group consisting of respiratory diseases and/or disorders, cardiac and cardiovascular diseases and/or disorders, autoimmune diseases and/or disorders, carcinogenesis, and associated symptoms or complications thereof, in a subject in need thereof which comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula (I) or a form thereof.

More specifically, this invention is directed to a method of treating exacerbations, non-allergic asthma, aspirin exacerbated respiratory disease, pulmonary arterial hypertension, fibrotic lung diseases, acute respiratory distress syndrome, obstructive sleep apnea and chronic obstructive pulmonary disease, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder, wherein the method comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula (I) or a form thereof.

Furthermore, this invention is directed to a method of treating myocardial infarction, atherosclerosis and coronary artery disease, stroke, aortic aneurisms, atherosclerosis, or associated symptoms or complications thereof, in a subject afflicted with such a disease and/or disorder, wherein the method comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula (I) or a form thereof.

Yet, this invention is also directed to a method of treating rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty effusions, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease, multiple sclerosis, allergic rhinitis, chronic sinusitis, allergic dermatitis and asthma, wherein the method comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula (I) or a form thereof.

Finally, this invention is also directed to a method of treating tumor cell proliferation, differentiation, and apoptosis, tumor-associated angiogenesis, as well as the migration and invasion of carcinoma cells, wherein the method comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula (I) or a form thereof.

Another aspect of the present invention provides a pharmaceutical composition comprising at least one compound of Formula (I) or a form thereof, and a pharmaceutically acceptable carrier.

The invention also features a method for treating a subject in need thereof with an FLAP-mediated disease and/or disorder, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of the invention.

Yet another aspect of the present invention relates to the use of a compound of Formula (I) or a form thereof, for the manufacture of a medicament useful for the treatment of an FLAP-mediated disease and/or disorder in a subject in need thereof.

In a clinical use of the compounds of the invention, pharmaceutically-acceptable additives may be added thereto to formulate various preparations in accordance with the intended administration route thereof, and the preparations may be administered.

Various additives generally used in the field of pharmaceutical compositions may be used herein, including, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, methyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, palmitoleic acid, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, and hydroxypropylcyclodextrin.

Combined with such additives, the compound of the invention may be formulated into various forms of preparations, for example, solid preparations such as tablets, capsules, granules, powders and suppositories; and liquid preparations such as syrups, elixirs and injections. These preparations can be produced in any method known in the field of pharmaceutical compositions. The liquid preparations may be in such a form that is dissolved or suspended in water or in any other suitable medium before use. Especially for injections, the preparation may be dissolved or suspended, if desired, in a physiological saline or glucose solution, and a buffer and a preservative may be added thereto.

The compounds of the invention are effective for animals, including humans and other mammals. Any ordinary physician, veterinarian or clinician may readily determine the necessity, if any, of treatment with an instant compound.

Those of skill in the treatment of diseases and/or disorders, or associated symptoms or complications thereof, mediated by FLAP can determine the effective daily amount from the test results presented hereinafter and other information. The exact dosage and frequency of administration depends on the particular compound of invention used, the particular disease and/or disorder, or associated symptoms or complications thereof, being treated, the severity of the disease and/or disorder, or associated symptoms or complications thereof, being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned herein are therefore only guidelines in practicing the present invention.

Preferably, the method for the treatment of the FLAP diseases and/or disorders described in the present invention using any of the compounds as defined herein, the dosage form will contain a pharmaceutically acceptable carrier containing between from about 1 mg to about 1000 mg; particularly from about 0.5 mg to about 500 mg of the compound, and may be constituted into any form suitable for the mode of administration selected. The dosages, however, may be varied depending upon the requirement of the subjects, the severity of the disease and/or disorder, or associated symptoms or complications thereof, being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

When the compound of the invention is, for example, put into clinical use, then its dose and its administration frequency may vary depending on the sex, the age, the body weight and the condition of the patient and on the type and the range of the necessary treatment with the compound. For oral administration, in general, the dose of the compound may be in a range of from about 0.01 mg/kg/day to about 100 mg/kg of body weight/day or in a range of from about 0.03 mg/kg/day to about 1 mg/kg/day. The oral administration frequency is preferably from one to a few times per day. For parenteral administration, the dose may be in a range of from about 0.001 mg/kg/day to about 10 mg/kg/day, in a range of from about 0.001 mg/kg/day to about 0.1 mg/kg/day or, in a range of from about 0.01 mg/kg/day to about 0.1 mg/kg/day. The parenteral administration frequency is preferably from one to a few times per day. For oral administration, the compositions are preferably provided in the form of tablets containing from about 1.0 mg to about 1000 mg of the active ingredient, particularly 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 750 mg, 800 mg, 900 mg, and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

Ordinary physicians, veterinarians and clinicians may readily determine the effective dose of the pharmaceutical compound necessary to treat, prevent, inhibit, retard or stop the intended disease, and may readily treat the diseased patient with the compound.

The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.001 mg/kg/day to about 10 mg/kg/day (particularly from about 0.01 mg/kg/day to about 1 mg/kg/day; and, more particularly, from about 0.1 mg/kg/day to about 0.5 mg/kg/day) and may be given at a dosage of from about 0.001 mg/kg/day to about 30 mg/kg/day (particularly from about 0.01 mg/kg/day to about 2 mg/kg/day, more particularly from about 0.1 mg/kg/day to about 1 mg/kg/day and even more particularly from about 0.5 mg/kg/day to about 1 mg/kg/day).

Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories for administration by oral, intranasal, sublingual, intraocular, transdermal, parenteral, rectal, vaginal, dry powder inhaler or other inhalation or insufflation means. Alternatively, the composition may be presented in a form suitable for 1 to 4 times per day, preferably once or twice per day administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.

The preparation may contain the compound of the invention in an amount in a range of from about 1.0 to about 100% by weight or, in a range of from about 1.0 to about 60% by weight of the preparation. The preparation may contain any other therapeutically-effective compound.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.

Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or as individual enantiomers or diasteromers by either stereospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all stereoisomers, racemic mixtures, diastereomers, cis-trans isomers, and enantiomers thereof are encompassed within the scope of the present invention.

E) Use

Dosages

For preparing pharmaceutical compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, antiadherents and gildants. Suitable diluents include, but are not limited to, starch (i.e. corn, wheat, or potato starch, which may be hydrolized), lactose (granulated, spray dried or anhydrous), sucrose, sucrose-based diluents (confectioner's sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate and the like. Suitable binders and adhesives include, but are not limited to acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics (i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like), water soluble or dispersible binders (i.e. alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e. TYLOSE™ available from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrol idone, polymethacrylates and pregelatinized starch) and the like. Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and tragacanth gum), cross-linked polyvinylpyrrolidone and the like. Suitable lubricants and antiadherents include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the like. Suitable gildants include, but are not limited to, talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot, SYLOID™ silica available from W.R. Grace/Davison, and AEROSIL™ silica available from Degussa) and the like. Sweeteners and flavorants may be added to chewable solid dosage forms to improve the palatability of the oral dosage form. Additionally, colorants and coatings may be added or applied to the solid dosage form for ease of identification of the drug or for aesthetic purposes. These carriers are formulated with the pharmaceutical active to provide an accurate, appropriate dose of the pharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active to form a solid preformulation composition containing a homogeneous mixture of the pharmaceutical active form of the present invention, or a pharmaceutically acceptable salt thereof. Generally the preformulation will be formed by one of three common methods: (a) wet granulation, (b) dry granulation and (c) dry blending. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 mg to about 500 mg of the active ingredient of the present invention. The tablets or pills containing the novel compositions may also be formulated in multilayer tablets or pills to provide a sustained or provide dual-release products. For example, a dual release tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric materials such as shellac, cellulose acetate (i.e. cellulose acetate phthalate, cellulose acetate trimellitate), polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylate and ethylacrylate copolymers, methacrylate and methyl methacrylate copolymers and the like. Sustained release tablets may also be made by film coating or wet granulation using slightly soluble or insoluble substances in solution (which for a wet granulation acts as the binding agents) or low melting solids a molten form (which in a wet granulation may incorporate the active ingredient). These materials include natural and synthetic polymers waxes, hydrogenated oils, fatty acids and alcohols (i.e. beeswax, camauba wax, cetyl alcohol, cetylstearyl alcohol, and the like), esters of fatty acids metallic soaps, and other acceptable materials that can be used to granulate, coat, entrap or otherwise limit the solubility of an active ingredient to achieve a prolonged or sustained release product.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, but are not limited to aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable suspending agents for aqueous suspensions, include synthetic and natural gums such as, acacia, agar, alginate (i.e. propylene alginate, sodium alginate and the like), guar, karaya, locust bean, pectin, tragacanth, and xanthan gum, cellulosics such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose, and combinations thereof, synthetic polymers such as polyvinyl pyrrolidone, carbomer (i.e. carboxypolymethylene), and polyethylene glycol; clays such as bentonite, hectorite, attapulgite or sepiolite; and other pharmaceutically acceptable suspending agents such as lecithin, gelatin or the like. Suitable surfactants include but are not limited to sodium docusate, sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxamer 188, polyoxamer 235 and combinations thereof. Suitable deflocculating or dispersing agents include pharmaceutical grade lecithins. Suitable flocculating agents include but are not limited to simple neutral electrolytes (i.e. sodium chloride, potassium, chloride, and the like), highly charged insoluble polymers and polyelectrolyte species, water soluble divalent or trivalent ions (i.e. calcium salts, alums or sulfates, citrates and phosphates (which can be used jointly in formulations as pH buffers and flocculating agents). Suitable preservatives include but are not limited to parabens (i.e. methyl, ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenylethanol and the like. There are many liquid vehicles that may be used in liquid pharmaceutical dosage forms; however, the liquid vehicle that is used in a particular dosage form must be compatible with the suspending agent(s). For example, nonpolar liquid vehicles such as fatty esters and oils liquid vehicles are best used with suspending agents such as low HLB (Hydrophile-Lipophile Balance) surfactants, stearalkonium hectorite, water insoluble resins, water insoluble film forming polymers and the like. Conversely, polar liquids such as water, alcohols, polyols and glycols are best used with suspending agents such as higher HLB surfactants, clays silicates, gums, water soluble cellulosics, water soluble polymers and the like. For parenteral administration, sterile suspensions and solutions are desired. Liquid forms useful for parenteral administration include sterile solutions, emulsions and suspensions. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

Furthermore, compounds of the present invention can be administered in an intranasal dosage form via topical use of suitable intranasal vehicles or via transdermal skin patches, the composition of which are well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the administration of a therapeutic dose will, of course, be continuous rather than intermittent throughout the dosage regimen.

Compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles and the like. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholines and the like.

The daily dose of a pharmaceutical composition of the present invention may be varied over a wide range from about 0.1 mg to about 5000 mg; preferably, the dose will be in the range of from about 1 mg to about 100 mg per day for an average human. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. Advantageously, a compound of the present invention may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily.

It is also apparent to one skilled in the art that the therapeutically effective dose for active compounds of the invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of the invention as FLAP modulators is required for a subject in need thereof.

In their use, the compounds of the invention may be combined with any other therapeutic agents that are useful for the treatment of an FLAP-mediated disorder.

The combination includes not only the composition of compounds of the invention and one other active substance but also the composition of compounds of the invention and two or more other active substances or non-drug therapy. The scope of possible combinations of a compound of the invention and one, two or more active substances are within the knowledge of one skilled in the art for the treatment of an FLAP-mediated disorder.

Specifically, the combination of a FLAP modulator with prostaglandin modulators, cyclooxygenase-1 modulators, or cyclooxygenase-2 modulators might be used to treat inflammatory and autoimmune diseases and/or disorders as well as cardiovascular diseases and/or disorders, or vascular injury (Z. Yu et al., “Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice,” Proc. Natl. Acad. Sci. USA, 2012, 109(17), 6727-32; Z. Yu et al., “Myeloid Cell 5-Lipoxygenase Activating Protein Modulates the Response to Vascular Injury,” Circ. Res., 2012, Epub Dec. 18). Due to the synergy of histamine and leukotrienes, the combination of a FLAP modulator and a histamine receptor 1 or 4 antagonist might have utility in treating respiratory, allergic, dermatological and autoimmune disorders (A. Reicin et al., “Montelukast, a leukotriene receptor antagonist, in combination with loratadine, a histamine receptor antagonist, in the treatment of chronic asthma,” Arch. Intern. Med., 2000, 160(16), 2418-88; S. Sanada et al., “The effectiveness of montelukast for the treatment of anti-histamine-resistant chronic urticaria,” Arch. Dermatol. Res., 2005, 297(3), 134-38).

Formulations

To prepare the pharmaceutical compositions of this invention, one or more compounds of Formula (I) or salt thereof as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

The compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes. Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

F) Biological Examples

The ability of the compounds of the present invention to treat a FLAP-mediated disease and/or disorder, or associated symptoms or complications thereof, was determined using the following procedures. Binding assay data represent the average value obtained from two different assay plates, with samples run in duplicate on each plate. Human whole blood assay data represent a single replicate on an assay plate using whole blood from at least one healthy donor.

FLAP Binding Assay

The assay below is used to test the modulatory activity of compounds against FLAP. Human and mouse FLAP-encoding DNA was amplified by polymerase chain reaction and cloned into pFastBac1 (Invitrogen) with a NH2-terminal 6-His tag for expression in Spodoptera frugiperda (Sf-9) cells. FLAP-containing membranes were prepared as was a FITC-labeled FLAP modulator (3-(3-(tert-butylthio)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropanoic acid). The FLAP binding assay is performed in HTRF format (homogeneous time resolved fluorescence). FLAP-containing membranes (1 μg/well final for human) are incubated in the presence of the HTRF ligand, [5-[({[2-(2-{3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropanoyl}hydrazino)-2-oxoethyl]sulfanyl}acetyl)amino]-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid] (25 nM final), a terbium labeled anti-His tag antibody (0.5 ng/well final, from Cisbio) and compounds. The reaction is allowed to proceed for two hours after which the plate is read on an Envision plate reader in HTRF mode. Data are expressed as a HTRF ratio.

For human FLAP binding assays, data are analyzed with 3DX Explorer software. A ratio is calculated with the relative light units at 520 nm over the relative light units at 495 nm. For analysis, data from multiple runs are averaged and each compound may be tested in 2 to 20 runs. Each run comprises two plates and each plate includes duplicates. Data from each plate is averaged and data are imported into 3DX. The data from multiple runs are aggregated as the average of duplicates of the calculated ratios in order to calculate K_(i) and IC₅₀ values. The letters ND and/or the absence of data in any of the boxes in Table 5 and Table 6 indicates that K_(i) or IC₅₀ values were not determined.

Human Whole Blood Assay

An in vitro cellular assay was performed using human whole blood collected in heparin-containing tubes, which was used to test the ability of compounds to modulate the leukotriene pathway in human whole blood. The blood was diluted 1:1 in RPMI medium, pre-incubated for 15 min at 37° Celsius with test compounds at various concentrations, and then stimulated with calcium ionophore, A23187 (7 μg/mL), for 30 min at 37° Celsius. The samples were then centrifuged and plasma was removed. The plasma was diluted in assay buffer and LTB₄ levels were measured using a commercial kit (Enzo Life Sciences). The concentration of each compound that was required for half-maximal inhibition (modulation) of recombinant enzyme activity (IC₅₀) was calculated by a 4-parameter equation using the program GraphPad Prism (GraphPad software).

TABLE 5 FLAP binding and Human Whole Blood assay data FLAP Binding wild type HTRF Human Whole Blood Cmp No. K_(i) (μM) LTB4 IC₅₀ 1:1 (μM) A 0.064 0.5311 B 0.354 0.9601 1 0.286 0.5882 2 0.158 0.5255 3 0.250 0.2712 4 0.004 0.2983 5 0.011 0.2632 6 0.014 1.2165 7 0.007 1.4025 8 0.750 9 0.808 10 0.866 11 0.750 12 0.090 13 0.250 1.2900 14 0.122 2.2888 15 0.193 1.2379 16 0.098 0.4670 17 0.016 0.2755 18 0.120 1.1684 19 0.100 0.8115 20 0.005 >10 21 0.008 4.1267 22 0.006 >10 23 0.002 0.3633 24 0.100 >10 25 0.012 0.5758 26 0.020 >10 27 0.006 0.8048 28 0.304 29 0.224 1.0605 30 0.354 31 0.170 1.9552 32 0.354 33 0.250 1.4135 34 0.304 1.5696 35 0.173 1.1387 36 0.220 2.5433 37 0.250 2.4963 38 0.250 0.7364 39 0.750 40 0.612 41 0.250 1.3462 42 2.000 43 0.430 44 1.500 45 0.193 0.7196 46 0.008 5.6157 47 0.042 0.2998 48 0.012 0.1751 49 0.132 1.1471 50 1.500 51 0.324 52 0.366 0.6797 53 0.138 0.6449 54 0.296 0.9087 55 0.152 0.5550 56 0.082 0.6437 57 0.036 0.3454 58 0.030 0.3736 59 0.327 1.5371 60 0.116 0.7318 61 0.262 0.6971 62 0.315 0.8316 63 0.120 0.2125 64 0.086 0.2753 65 0.018 0.1067 66 0.422 0.7534 67 0.176 0.7268 68 0.750 69 0.030 0.0739 70 0.034 0.4127 71 0.620 72 0.018 0.7372 73 0.275 1.0249 74 0.750 75 0.370 76 0.250 1.7656 77 0.200 1.3823 78 0.173 1.2888 79 0.250 2.2295 80 0.304 3.2931 81 0.394 82 0.304 83 0.037 0.6046 84 0.070 0.8865 85 0.028 10 86 0.005 0.0351 87 0.001 0.0067 88 0.004 0.0361 89 0.004 0.0222 90 0.0538 91 0.001 0.0048 92 6.6635 93 0.003 0.0308 94 0.027 0.1010 95 0.005 >1 96 0.007 0.0338 97 0.032 0.1534 98 0.008 0.1751 99 0.006 0.0407 100 0.001 0.0126 101 0.023 0.9143 102 0.002 0.1028 103 0.035 0.6750 104 0.100 2.8054 105 0.250 106 0.084 0.3759 107 0.0069 0.1770 108 0.0246 1.3056 109 0.0089 0.3075 110 0.0024 0.0522 111 0.0019 0.0654 112 0.0148 0.1812 113 0.0270 0.6076 114 0.0172 0.3746 115 0.297 1.1064 116 0.0146 0.5034 117 2.500 118 0.0105 0.0657 119 0.006 0.0263 120 0.304 121 0.250 122 0.004 0.4596 123 0.007 4.4771 124 0.003 0.1192 125 0.250 126 0.0107 0.4059 127 2.200 128 0.297 129 0.119 0.2813 130 0.0037 0.0841 131 0.0056 0.0679 132 0.0170 0.1327 133 0.0102 0.0796 134 0.0062 0.0397 135 0.0013 0.0124 136 0.0035 0.0459 137 0.0037 0.0510 138 0.0055 0.0703 139 0.0039 0.0485 140 0.0013 0.0117 141 0.0050 0.0586 142 0.0017 0.0185 143 0.0029 0.0377 144 0.0011 0.0223 145 0.0054 0.1774 146 0.0004 0.0045 147 0.0064 0.1854 148 0.1007 149 0.0013 0.1119 150 0.1764 3.5859 151 0.0089 0.0754 152 0.0625 >10 153 0.0023 0.4245 154 0.0125 >10 155 0.0041 0.1701 156 2.236 157 0.0206 0.1090 158 0.0078 0.0359 159 0.0557 3.3052 E 0.0995 1.0950 160 0.0947 0.4935 161 0.0222 0.0880 162 0.0072 0.1238 163 0.0704 0.4941 164 0.0368 0.1185 165 0.0056 0.3039 166 0.0117 0.1286 167 0.0147 0.0456 168 0.0028 0.0361 169 0.2053 0.2680 170 0.0903 1.4256 171 0.0398 0.2519 172 0.394 1.6615 173 0.682 174 0.0054 1.2142 175 0.1 1.2835 F 0.075 1.2960 176 0.1 0.8917 177 0.093 0.7711 178 0.354 179 0.750 180 0.370 181 0.041 10.0000 182 1.936 183 0.328 >10 184 0.0140 0.8310 185 0.0196 1.0074 186 0.0205 0.5309 187 0.0120 0.3551 188 0.0086 1.1036 189 0.0098 1.1397 190 0.0472 1.0575 191 0.2500 3.4316 192 0.0053 0.4184 193 0.0037 0.7688 194 0.0029 0.1682 195 0.0022 0.4457 196 0.0041 0.8712 197 0.750 198 0.0187 2.3681 199 0.0242 1.0566 G 0.0779 0.5748 200 0.1551 1.3583 201 0.0085 0.0518 202 0.0061 0.0805 203 0.0069 0.0308 204 0.0815 0.1713 205 0.0402 0.1496 H 0.0723 0.2866 206 0.7690 207 0.0474 0.0726 208 0.0465 0.2146 209 0.0233 0.0511 210 2.500 211 0.527 212 0.0640 1.0950 213 0.0921 1.0146 214 0.0308 1.0872 215 0.620 216 0.866 217 1.250 218 0.0773 >5.000 219 >10 220 0.0218 1.117 221 0.5932 222 0.1798 3.475 223 >10 224 0.0232 0.2867 225 0.0025 0.0684 226 0.0014 0.0901 227 0.0085 0.3317 228 0.0244 0.4804 229 0.0077 0.4075 230 0.0025 0.2379 231 2.1389 232 1.5907 233 1.6792 234 1.3002 >10 235 0.0033 0.1132 236 0.0022 0.0371 237 0.0033 0.0847 238 0.1551 0.5710 239 0.0083 0.1967 240 0.0236 0.1045 241 0.0012 0.0207 242 0.0036 0.0300 I 0.090 1.6688 243 0.2355 0.8588 244 0.4622 1.8168 245 0.0622 2.8016 246 0.0986 1.5929 247 0.2594 0.4173 248 0.2610 10 249 0.2076 1.2636 250 0.0992 0.3567 251 1.1951 252 0.0296 >1 253 0.8541 254 0.9922 255 1.1392 1.1387 256 0.4335 0.7180 257 0.0311 0.3324 258 0.0038 0.0101 259 0.0070 0.1344 260 0.0199 0.1973 261 0.0013 0.0401 262 0.0196 0.1596 263 0.1375 1.9579 264 >10 265 >10 266 >10 267 >10 268 >10 269 0.0009 0.0151 270 0.7995 271 0.0051 0.0853 272 0.0005 0.0419 273 >10 274 0.0196 0.1596 275 0.1375 1.9579 276 0.0392 0.4063 277 0.0177 0.1346 278 0.1000 0.2160 279 0.0675 0.1466 280 >10 281 0.1006 0.3696 282 0.0294 >10 283 0.0976 284 >10 285 >10 286 287 288 0.3646 289 0.2292 0.7825 290 0.0399 0.5059 291 0.0466 0.5761 292 0.0372 0.4125 293 0.0165 1 294 0.6914 295 0.0042 0.1488 296 0.0068 0.3499 297 0.0144 0.2626 298 >10 299 >10 300 >10 301 >10 302 >10 303 >10 304 >10 305 >10 306 >10 307 >10 308 >10 309 >10 310 >10 311 0.0081 0.1099 312 0.9745 313 0.0024 0.0270 314 >10 315 1.3649 316 0.2893 317 0.1978 0.4639 318 0.0581 0.1031 319 0.3367 0.2845 320 0.0364 0.1674 321 0.1165 >10 322 0.5730 323 0.2106 0.1406 324 0.0738 0.2.600 325 0.0095 0.0527 326 0.3584 327 0.5278 328 0.1127 0.3125 329 0.0097 0.0390 330 0.0051 >1 331 0.0037 0.0129 332 0.0458 0.4500

The following compounds were tested in additional runs for the assays described above and the data is provided in Table 6.

TABLE 6 FLAP binding and Human Whole Blood assay data FLAP binding wild type HTRF Human Whole Blood Cmp No. K_(i)(μM) LTB4 IC₅₀ 1:1 (uM) A 0.0526 0.5311 B 0.0839 0.9601 1 0.0628 0.5882 2 0.0861 0.8954 3 0.1184 0.2712 4 0.0058 0.2983 5 0.0102 0.2632 6 0.0136 1.2165 7 0.0074 1.4025 8 ~0.7500 9 ~0.8077 10 ~0.8659 11 ~0.7500 12 ~0.0899 13 0.0271 1.2900 14 0.0226 2.2888 15 ~0.1933 1.2379 16 0.0199 0.4670 17 0.0125 0.2820 18 0.0590 1.1684 19 0.0038 0.8115 20 0.0051 >10 21 0.0081 4.1267 22 0.0059 >10 23 0.0037 0.3633 24 0.0162 >10 25 0.0122 0.5758 26 ~0.0199 >10 27 0.0064 0.8048 28 0.0662 29 0.0246 1.0605 30 0.0335 31 ~0.1699 1.9552 32 ~0.3535 33 ~0.2499 1.4135 34 ~0.3041 1.5696 35 ~0.1732 1.1387 36 ~0.2199 2.5433 37 ~0.2499 2.4963 38 ~0.2499 0.7364 39 ~0.7500 40 ~0.6123 41 ~0.2499 1.3462 42 ~1.9998 43 ~0.4301 44 ~1.5000 45 ~0.1933 0.7196 46 0.0069 5.6157 47 0.0418 0.2998 48 0.0121 0.1751 49 ~0.1319 1.1471 50 0.7872 51 0.3240 52 0.3661 0.6797 53 0.1381 0.6449 54 0.2957 0.9087 55 0.1516 0.5550 56 0.0819 0.6437 57 0.0356 0.3454 58 0.0303 0.3736 59 0.3269 1.5371 60 0.1161 0.7318 61 0.2618 0.6971 62 0.3145 0.8316 63 0.1202 0.2125 64 0.0860 0.2753 65 0.0182 0.1067 66 0.4216 0.7534 67 0.1762 0.7268 68 0.1355 69 0.0140 0.0739 70 0.0342 0.4127 71 0.4208 72 0.0237 0.7372 73 0.2748 1.0249 74 0.1747 75 ~0.3699 76 ~0.2499 1.7656 77 ~0.1999 1.3823 78 ~0.1732 1.2888 79 ~0.2499 2.2295 80 ~0.3041 3.2931 81 ~0.3937 82 0.2085 83 0.0445 0.6046 84 ~0.0700 0.8865 85 0.0281 ~10 86 0.0062 0.0351 87 0.0021 0.0067 88 0.0035 0.0361 89 0.0053 0.0222 90 0.0538 91 0.0008 0.0048 92 6.6635 93 0.0052 0.0308 94 0.0445 0.1010 95 0.0047 >1 96 0.0071 0.0338 97 0.0317 0.1261 98 0.0084 0.1239 99 0.0055 0.0407 100 0.0012 0.0126 101 0.0233 0.9143 102 0.0018 0.1028 103 ~0.0353 0.6750 104 0.0183 2.8054 105 0.0394 106 0.0123 0.3759 107 0.0054 0.1770 108 0.0281 1.3056 109 0.0112 0.3075 110 0.0026 0.0522 111 0.0024 0.0654 112 0.0136 0.1812 113 0.0308 0.6076 114 0.0102 0.3746 115 0.0537 1.1064 116 0.0139 0.5034 117 ~2.4997 118 0.0105 0.0657 119 0.0066 0.0274 120 ~0.3041 121 0.0072 122 0.0037 0.4596 123 0.0070 4.4771 124 0.0028 0.1192 125 ~0.2499 126 0.0107 0.4059 127 ~2.2003 128 ~0.2973 129 ~0.1192 0.2813 130 0.0037 0.0214 131 0.0056 0.0679 132 0.0170 0.1327 133 0.0102 0.0796 134 0.0046 0.0397 135 0.0013 0.0124 136 0.0039 0.0566 137 0.0043 0.0510 138 0.0053 0.0703 139 0.0038 0.0485 140 0.0013 0.0117 141 0.0055 0.0586 142 0.0017 0.0185 143 0.0029 0.0377 144 0.0011 0.0223 145 0.0054 0.1774 146 0.0004 0.0045 147 0.0064 0.1854 148 0.1007 149 0.0013 0.1119 150 0.1764 3.5859 151 0.0089 0.0754 152 0.0625 >10 153 0.0023 0.4245 154 0.0176 >10 155 0.0049 0.1279 156 ~2.2361 157 0.0206 0.1090 158 0.0078 0.0359 159 0.0557 3.3052 E 0.0995 1.0950 160 0.0947 0.4935 161 0.0222 0.0880 162 0.0072 0.1238 163 0.0704 0.4941 164 0.0368 0.1185 165 0.0056 0.3039 166 0.0117 0.1286 167 0.0147 0.0456 168 0.0028 0.0361 169 0.2053 0.2680 170 0.0903 1.4256 171 0.0398 0.2519 172 ~0.3937 1.6615 173 ~0.6818 174 0.0039 1.2142 175 ~0.1 1.2835 176 ~0.0750 1.2960 177 ~0.1 0.8917 178 ~0.0930 0.7711 179 ~0.3535 F ~0.7500 180 ~0.3699 181 0.0407 10.0000 182 ~1.9364 183 ~0.3279 >10 184 0.0140 0.8310 185 0.0196 1.0074 186 0.0205 0.5309 187 0.0120 0.3551 188 0.0086 1.1036 189 0.0098 1.1397 190 0.0472 1.0575 191 ~0.2499 3.4316 192 0.0053 0.4184 193 0.0037 0.7688 194 0.0029 0.1682 195 0.0022 0.4457 196 0.0041 0.8712 197 ~0.7500 198 0.0187 2.3681 199 0.0242 1.0566 G 0.0779 0.5748 200 0.1551 1.3583 201 0.0085 0.0518 202 0.0061 0.0805 203 0.0069 0.0308 204 0.0815 0.1713 205 0.0402 0.1496 H 0.0723 0.2866 206 0.7690 207 0.0515 0.0780 208 0.0465 0.1605 209 0.0233 0.0511 210 ~2.4997 211 ~0.5267 212 0.0640 1.0950 213 0.0921 1.0146 214 0.0308 1.0872 215 0.7049 216 0.7135 217 1.0378 218 0.0773 >5.00034 219 >10 220 0.0218 1.1169 221 0.5932 222 0.1798 3.4754 223 >10 224 0.0232 0.2867 225 0.0232 0.2867 226 0.0014 0.0901 227 0.0085 0.3317 228 0.0244 0.4804 229 0.0077 0.4075 230 0.0025 0.2379 231 2.1389 232 1.5907 233 1.6792 234 1.3002 >10 235 0.0033 0.1132 236 0.0022 0.0371 237 0.0033 0.0847 238 0.1551 0.5710 239 0.0083 0.1967 240 0.0236 0.1045 241 0.0012 0.0207 242 0.0036 0.0300 I ~0.0899 1.6688 243 0.2355 0.8588 244 0.4622 1.8168 245 0.0622 2.8016 246 0.0986 1.5929 247 0.2594 0.4173 248 0.2610 ~10 249 0.2817 1.2636 250 0.0992 0.3567 251 1.1951 252 0.0296 >1 253 0.8541 254 0.9922 255 1.1392 1.1387 256 0.4335 0.7180 257 0.0311 0.3324 258 0.0038 0.0101 259 0.0070 0.1344 260 0.0199 0.1973 261 0.0022 0.0401 262 0.0196 0.1568 263 0.1375 1.9579 264 0.1013 265 >10 266 >10 267 >10 268 >10 269 0.0009 0.0151 270 0.7995 271 0.0051 0.0853 272 0.0005 0.0419 273 >10 274 0.0196 0.1568 275 0.1375 1.9579 276 0.0392 1.8557 277 0.0177 0.1909 278 0.1001 0.2160 279 0.0676 0.1141 280 >10 281 0.1006 0.4533 282 0.0294 >10 283 0.0976 0.5378 284 >10 285 >10 286 0.0817 1.1882 287 0.0176 >1 288 0.3646 289 0.2292 0.7825 290 0.0399 0.5059 291 0.0466 0.5761 292 0.0372 0.4125 293 0.0165 0.1004 294 0.6914 295 0.0042 0.1881 296 0.0068 0.2829 297 0.0144 0.2125 298 0.8680 299 1.9566 300 >10 301 >10 302 >10 303 >10 304 >10 305 >10 306 >10 307 >10 308 >10 309 >10 310 >10 311 0.0081 0.2658 312 0.9745 313 0.0024 0.0270 314 >10 315 1.3649 316 1.3649 317 0.1979 0.4640 318 0.0582 0.1041 319 0.3367 0.2846 320 0.0365 0.1674 321 0.1165 >10 322 0.5731 323 0.2107 0.1407 324 0.0738 0.2601 325 0.0096 0.0528 326 0.3584 327 0.5278 328 0.1128 0.3125 329 0.0097 0.0391 330 0.0051 >1 331 0.0037 0.0129 332 0.0459 0.4501 333 0.4211 334 0.0046 0.0527 335 0.0036 0.0369 336 0.0039 0.0238 337 0.0148 0.1615 338 0.0017 0.0959 339 0.1077 1.6376 340 0.6501 341 0.0226 0.1238 342 0.0081 0.0263 343 0.0054 0.0144 344 0.0269 0.0915 345 0.0142 0.0151 346 0.0453 0.1762 347 0.0476 0.3961 348 0.0131 0.1467 349 0.0310 >1 350 0.0529 0.4491 351 0.0544 0.1242

Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. 

1. A compound of Formula (I)

wherein L is selected from: a bond, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂NH—, —CH₂C(═O)NH—, —CH₂C(OH)(H)CH₂—, and —CH₂C(OH)(H)CH₂NH—; R₁ is selected from: halo, C₁₋₅-alkyl, C₃₋₆cycloalkyl, and cyclohexylmethyl; R₂ is selected from: H, C₁₋₄alkyl, hydroxyl, amino, cyano, —CH₂C(═O)O-(tert-butyl), —CH₂C(═O)O-(ethyl), —CH₂C(═O)OH, —NHS(═O)₂CH₃, tert-butyl(dimethyl)silyl-oxy, —NHCH₃, —N(CH₃)₂, —NH-(Isopropyl), optionally substituted phenyl, optionally substituted 5-membered or 6-membered heteroaryl, C₃₋₆cycloalkyl, and optionally substituted heterocyclyl; wherein the 5-membered or 6-membered heteroaryl, the heterocyclyl, or the phenyl is optionally and independently substituted with 1-4 substituents selected from the group consisting of: C₁₋₄alkyl, —CH₂-methoxy, —C(═O)OH, —CH₂C(═O)OH, —C(═O)—O—CH₂CH₃, —C(═O)—O—CH₃, —C(═O)—O-(tert-butyl), —NH₂, —N(CH₃)₂, —NH-(isobutyl), —NH(CH₂)₂NHC(═O)—O-tert-butyl, —NH(CH₂)₂NH₂, —NH(CH₂)₂N(CH₃)₂, —C(═O)NH₂, —C(═O)CH₃, oxo, halo, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, methoxymethyl, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂, —S—CH₃, cyano, 1H-tetrazol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl, 4′-(trifluoromethyl) phenyl, benzyl, 1,5-dioxa-9-azaspiro[5.5]undecan-9-yl, 5-pyrimidine-2-amine, and pentafluoro-lambda˜6˜-sulfanyl; ring A is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 2. (canceled)
 3. (canceled)
 4. A compound of claim 1, wherein the compound is selected from the group consisting of: 6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine, 7-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol, 7-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile, 7-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile, 7-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide, 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide, 7-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, (4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic acid, 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzoic acid, 3-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine, 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 6-Cyclobutyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol, 6-Cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol, 6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol, 7-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 2-(6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy)pyrimidin-4-amine, 7-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 5-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine, 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 2-[6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenoxy]pyrimidin-4-amine, and 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine, and and their pharmaceutically acceptable salts thereof.
 5. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.
 6. The pharmaceutical composition of claim 5 comprising at least one compound of claim
 4. 7. A method of treating a subject suffering from or diagnosed with a disease and/or disorder mediated by FLAP activity, comprising administering to the subject a therapeutically effective amount of at least one compound of claim
 1. 8. A method according to claim 7, wherein the disease and/or disorder is selected from the group consisting of respiratory, cardiac and cardiovascular, autoimmune and allergic, carcinogenesis disease and/or disorder, and associated symptoms or complications thereof.
 9. A method according to claim 8, wherein the respiratory disease and/or disorder is selected from the group consisting of exacerbations, non-allergic asthma, fibrotic lung diseases, acute respiratory distress syndrome and chronic obstructive pulmonary disease, or associated symptoms or complications thereof.
 10. A method according to claim 8, wherein the cardiac and cardiovascular disease and/or disorder is selected from the group consisting of myocardial infarction, atherosclerosis and stroke aortic aneurisms, atherosclerosis, or associated symptoms or complications thereof.
 11. A method according to claim 8, wherein the autoimmune and allergic disease and/or disorder is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty effusions, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease, multiple sclerosis, allergic rhinitis, allergic dermatitis and asthma, or associated symptoms or complications thereof.
 12. A method according to claim 8, wherein the carcinogenesis disease and/or disorder is selected from the group consisting of tumor cell proliferation, differentiation, apoptosis, tumor-associated angiogenesis, and the migration or invasion of carcinoma cells.
 13. The method of claim 7, wherein the therapeutically effective amount of the compound of Formula (I) is from about 0.1 mg/dose to about 5 g/dose.
 14. A process for making a pharmaceutical composition comprising admixing any of the compounds according to claim 1 and a pharmaceutically acceptable carrier.
 15. (canceled)
 16. (canceled) 